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Stimulation of the hepatoportal nerve plexus with focused ultrasound restores glucose homoeostasis in diabetic mice, rats and swine

Nature Biomedical Engineering volume 6, pages 683–705 (2022)Cite this article

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Abstract

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.

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Fig. 1: Daily ultrasound stimulation of the liver–brain neural pathway prevents or reverses the onset of hyperglycaemia in multiple animal models of T2D.
Fig. 2: pFUS improves glucose tolerance after acute and chronic stimulation exposure.
Fig. 3: pFUS alters glucose kinetics in small- and large-animal models.
Fig. 4: pFUS effect is dependent on liver–brain nerve pathways.
Fig. 5: Hepatoportal plexus pFUS modulates firing rates of hypothalamic GE neurons.
Fig. 6: pFUS effect is dependent on the activity of mechanically activated ion channels in both in vitro and in vivo models.
Fig. 7: Tissue-specific transcriptomic and metabolomic changes after pFUS treatment of multiple animal models of T2D.
Fig. 8: Tissue-specific transcriptomic and metabolomic changes at multiple timepoints during 7 weeks of daily pFUS treatment of multiple animal models of T2D.

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Data availability

The main data supporting the results in this study are available within the manuscript and its Supplementary Information. Source data for the figures are provided with this paper. The RNA-sequencing datasets generated during the study are available in the US National Center for Biotechnology Information Search (NCBI) Gene Expression Omnibus (GEO) repository (series record: GSE197097). Source data are provided with this paper.

Code availability

The source codes used for the data analyses of the study are available on request.

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Acknowledgements

We thank G. Petter Fosse (University Hospital of Northern Norway) for helpful discussions on large-animal experiments. Experiments in this study were partially funded with Federal funds from the Defense Advanced Research Project Agency (United States Department of Defense; DARPA DoD; DARPA HR0011-18-C-0040). R.I.H. was supported by the NIH via UL1 TR001863; P30 DK045735; R01 DK101984; R01 DK020495; and DARPA 401126008. The views, opinions and/or findings expressed herein are those of the authors and should not be interpreted as representing the official views or policies of the Department of Defense or the US Government.

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Authors and Affiliations

  1. General Electric (GE) Research, 1 Research Circle, Niskayuna, NY, USA

    Victoria Cotero, John Graf, Radhika Madhavan, Kirk Wallace, Evelina Loghin, Christine Morton, Ying Fan, Tzu-Jen Kao, Jeffrey Ashe & Chris Puleo

  2. University of California, Los Angeles, Los Angeles, CA, USA

    Hiromi Miwa & Dino Di Carlo

  3. Albany Medical College, Albany, NY, USA

    Zall Hirschstein, Kainat Akhtar, Meghana Damaraju, Linda Barenboim, Teresa Maietta & Damian Shin

  4. Feinstein Institutes for Medical Research, Manhasset, NY, USA

    Khaled Qanud, Tomás S. Huerta, Jacquelyn N. Tomaio, Weiguo Song, Alex Devarajan, Tea Tsaava, Kevin J. Tracey, Thomas R. Coleman, Stavros Zanos & Sangeeta S. Chavan

  5. Yale School of Medicine, New Haven, CT, USA

    Ningwen Tai, Yuyan Ding, Kevin Jimenez-Cowell & Raimund I. Herzog

  6. German Cancer Research Center (DKFZ), Heidelberg, Germany

    Kevin Jimenez-Cowell

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  1. Victoria Cotero
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Contributions

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.

Corresponding author

Correspondence to Chris Puleo.

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Competing interests

V.C., J.G., R.M., K.W., E.L., C.M., Y.F., T.-J.K., J.A. and C.P. are employees of General Electric and declare that GE has filed US and international patent applications describing methods, devices and systems for precision organ-based ultrasound neuromodulation. H.M., Z.H., K.Q., T.S.H., N.T., Y.D., K.J.-C., J.-N.T., A.D., T.T., K.A., M.D., L.B., T.M., K.J.T., T.R.C., D.D.C., D.S., S.Z., S.S.C. and R.I.H. have received research funding from GE to investigate the effects of ultrasound on metabolism. W.S. declares no competing interests.

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Extended data

Extended Data Fig. 1 Hepatic pFUS attenuates hyperglycemia in mice.

a. Hepatic pFUS attenuates hyperglycemia in western diet-fed mice. Blood glucose levels were measured at week 9 (white plots), prior to the stimulation period and week 16 (grey plots), post-stimulation period. Daily stimulated western diet-fed mice had significantly reduced blood glucose levels across the stimulation period (WD–pFUS, week 9 vs week 16; p-values shown are derived using nonparametric Wilcoxon rank-sum test and corrected using the Bonferroni method (n = 14 per group; Box plot presents the data median, first and third quartiles and the whiskers are the 1.5 x range (IQR). If no points exceed 1.5 x IQR distance, then the whiskers are simply the minimum and maximum values). b. Hepatic pFUS attenuates hyperinsulinemia in western diet-fed mice. Insulin levels were measured at week 9 (white plots), prior to the stimulation period, and at week 16 (grey plots), post-stimulation period. WD–pFUS mice had significantly reduced insulin levels across the stimulation period (WD–pFUS, week 9 vs week 16, p-values shown are derived using nonparametric Wilcoxon rank-sum test (two-sided) and corrected using the Bonferroni method (n = 10 per group; Box plot presents the data quartiles and whiskers are the minimum and maximum values unless value exceeds the 1.5 x IQR distance).

Source data

Extended Data Fig. 2 Effect of pulsed focused ultrasound (pFUS) of the porta hepatis on insulin sensitivity in STZ-induced diabetic diet-induced obesity (DIO) rats, as quantified through hyperinsulinemic-euglycemic clamp121 (HEC).

a) Timeline of experimental interventions. Glucose infusion rate (GIR) during standardized hyperinsulinemic clamp (glucose values shown in b; n = 7)) revealing higher steady state glucose infusion requirement after pFUS treatment and c) glucose infusion rate area under the curve (AUC) for steady state (n = 7; Box plot presents the data median, first and third quartiles and the whiskers are the 1.5 x range (IQR). If no points exceed 1.5 x IQR distance, then the whiskers are simply the minimum and maximum values). Plasma hormone change during the clamp including d) glucagon e) epinephrine, f) norepinephrine and g) corticosterone. Values are mean ± SEM; p-values from 2-way ANOVA (GIR); multiple t-tests (hormones); or Wilcoxon rank sum (AUC); n = 6 per measurement for D-G.

Source data

Extended Data Fig. 3 Effect of pulsed focused ultrasound (pFUS) of the porta hepatis on insulin sensitivity in STZ-induced T1D rats, as quantified through hyperinsulinemic-euglycemic clamp121 (HEC).

a) Timeline of experimental interventions (see material and methods for experimental description). Glucose infusion rate (GIR) during standardized hyperinsulinemic clamp (glucose values shown in b; n = 6)) revealing higher steady state glucose infusion requirement after pFUS treatment and c) glucose infusion rate area under the curve (AUC) for steady state (n = 6; Box plot presents the data median, first and third quartiles and the whiskers are the 1.5 x range (IQR). If no points exceed 1.5 x IQR distance, then the whiskers are simply the minimum and maximum values). Plasma hormone change during the clamp including d) glucagon, e) epinephrine, f) norepinephrine and g) corticosterone. Values are mean ± SEM.; p-values from 2-way ANOVA (GIR); multiple t-tests (hormones); or Wilcoxon rank sum (AUC); n = 5 per measurement for D-G.

Source data

Extended Data Fig. 4 Short-term effect of focused ultrasound (pFUS) of the porta hepatis on insulin sensitivity in healthy swine, as quantified through hyperinsulinemic-euglycmic clamp (HEC).

a. Representative data from an HEC experiment. Under continuous, constant infusion of insulin at a rate of 0.5 mU/kg/min, glucose infusion rate (GIR) was adjusted every 5 minutes according to a formula121 to achieve euglycemia (defined as baseline glucose concentration ±10%) and maintained for ≥ 30 min (grey shaded area). In this example, GIR at euglycemic equilibrium was 3.5 mg/kg/min. The quality of the HEC was assessed by calculating the normalized coefficient of variation (CV) of the glucose concentration and GIR for the duration of euglycemic equilibrium. In this experiment, CV for glucose was 6.92% and for GIR was 6.51%. b. In step-clamp experiments, euglycemic equilibrium GIR values were calculated for different insulin infusion rates (IIR) in 2 animals. Based on this data, we decided to conduct pFUS experiments at IIR of 0.5 mU/kg/min, as the slope of the GIR curves, and therefore the sensitivity of the method to resolve changes in insulin sensitivity, decreased at higher IIRs. c. Example of a pFUS experiment, after establishing HEC (CV for glucose 2.85%, for GIR 0%). pFUS of the porta hepatis was applied for 4 minutes (blue shaded area), after which GIR was adjusted, just like before, to maintain euglycemia. Increase in GIR after pFUS reflects increased insulin sensitivity. d. Imaging of the porta hepatis in swine. Left: Noninvasive imaging (probe placed on skin). Right: Invasive imaging (probe placed on top of PH after it was surgically accessed). e. Example of a sham-stimulation experiment in an animal that previously underwent pFUS stimulation. In the sham-stimulation experiment, once HEC was established, the US probe was operated in imaging mode (with ultrasound power off). In the pFUS experiment (results previously shown in Fig. 3) performed in the same animal 3 days later, HEC was established like before and noninvasive pFUS stimulation was delivered. See Methods for experimental descriptions.

Source data

Extended Data Fig. 5 Histochemical analysis of hypothalamic neural pathways associated with response to pFUS after 20 days of daily stimulation in the ZDF model.

a. cFOS immunohistochemistry images show the number of activated neurons in unstimulated (left) versus pFUS stimulated (right) animals. Images were segmented on the paraventricular nucleus (PVN; green), dorsal medial nucleus (DMN; yellow), ventromedial nucleus (VMN; red), arcuate nucleus (ARC; blue), and lateral hypothalamus (LH; purple) Scale bar = 200 microns. b. Data showing the percent change in the number of cFos expressing cells with pFUS compared to sham controls in each segmented hypothalamic region (PVN, DMN, VMN, ARC, LH), images shown represent one set of sham versus stimulated paired (n = 3; data shown as mean ± s.e.). c. Histochemical analysis of paraffin-embedded rat brain tissue labeling BDNF antibody showing the unstimulated control (left) and pFUS stimulated animals (right). As observed an increase in BDNF staining was visible in the hypothalamus (with prominence in the arcuate and ventromedial hypothalamus), thalamic and hippocampal brain regions. Images are included as partial coronal sections to demonstrate total BDNF activation by pFUS across a number of brain regions. d. Histochemical analysis of paraffin embedded rat brain tissue labeling GLUT-4 receptor antibody showing hypothalamic (left) and hippocampal (right) staining patterns. As observed an increase in both hypothalamic and hippocampal GLUT-4 translocation occurred following hepatic pFUS (right) as compared to unstimulated sham controls (left).

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Cotero, V., Graf, J., Miwa, H. et al. Stimulation of the hepatoportal nerve plexus with focused ultrasound restores glucose homoeostasis in diabetic mice, rats and swine. Nat. Biomed. Eng 6, 683–705 (2022). https://doi.org/10.1038/s41551-022-00870-w

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