Focused Ultrasound Modulation of Hepatic Neural Plexus Restores Glucose Homeostasis in Diabetes

Abstract

While peripheral glucose sensors are known to relay signals of substrate availability to integrative nuclei in the brain, the importance of these pathways in maintaining energy homeostasis and their contribution to disease remain unknown. Herein, we demonstrate that selective activation of the hepatoportal neural plexus via transient peripheral focused ultrasound (pFUS) induces glucose homeostasis in models of well-established insulin resistant diabetes. pFUS modulates sensory projections to the hindbrain and alters hypothalamic concentrations of neurotransmitters that regulate metabolism, resulting in potentiation of hypothalamic insulin signaling, leptin-independent inhibition of the orexigenic neuropeptide Y system, and therapeutic alteration in autonomic output to peripheral effector organs. Multiomic profiling confirms pFUS-induced modifications of key metabolic functions in liver, pancreas, muscle, adipose, kidney, and intestines. Activation of the hepatic nutrient sensing pathway not only restores nervous system coordination of peripheral metabolism in three different species but does so across these organ systems; several of which are current targets of antidiabetic drug classes. These results demonstrate the potential of hepatic pFUS as a novel/non-pharmacologic therapeutic modality to restore glucose homeostasis in metabolic diseases, including type II diabetes. One Sentence Summary We utilize a non-invasive ultrasound technique to activate a liver-brain sensory pathway and demonstrate its potential to induce durable normalization of glucose homeostasis in models of well-established insulin resistant diabetes.

Abstract via europepmc.

Flags from extraction

• exposures[0].timing.pulse_repetition_frequency_hz — The general hardware description states '5 Hz Pulse Repetition Frequency' as the nominal setting for the 1.1 MHz system, but the specific rat/mouse diabetes-treatment protocol text states a '500 us burst period' (converted here to 2000 Hz), and a separate section (Mechanical vs Ultrasound Neuromodulation) gives the pulse repetition period as '500 us (or 200 ms)' for the same transducer system. These are inconsistent; 2000 Hz (from the 500 us period stated in the actual treatment protocol) is used here.
• exposures[0].timing.pulse_duration_ms — 150 usec is given as the nominal 'Pulse Duration' setting and matches '150 burst cycles' at 1.1 MHz (~136 us); a different section states '133 us pulse length' for what is described as the same transducer system used for spleen/CAP stimulation.
• exposures[0].in_situ.isppa_w_cm2 — Derated performance values (MI, pressure, Isppa.3, Ispta.3) are characterized at the hardware's nominal settings (135 mV amplitude, 150 us pulse, 5 Hz PRF); the actual diabetes-treatment protocol used 200 mV amplitude and a different (500 us) burst period, so it is unclear whether these derated values directly apply to the treatment exposure.
• exposures[1].timing.sonication_duration_s — The 2.5 MHz electrophysiology-recording ultrasound system's per-application duration is not stated in the Methods text located.
• exposures[3].unspecified_domain.pressure_kpa — Figure 2 legend text is ambiguous: '...remains small without application of ultrasound stimulus (at 0.83 MPa peak-positive pressure)' could be read as describing the pressure used during stimulation trials rather than the no-stimulus baseline; 0.83 MPa is recorded as the pFUS pressure used on DRG cultures.
• n_subjects — This paper reports dozens of separate cohorts across many species, models and experiments (e.g. n=5-12 per group in various rat/mouse GTT, clamp, transcriptomic and electrophysiology sub-studies) without ever stating one overall total number of ultrasound-exposed subjects; no single reliable total or group-size list could be constructed.
• sham_type — Sham/'Sham-CTRL' stimulation is referenced throughout but its mechanism (e.g. transducer powered off vs aimed away) is never described.
• conditions — Type 2 diabetes / insulin resistance / diet-induced obesity is not in the closed conditions vocabulary; classified as 'other'.
• exposures[3].in_situ — DRG neurons were cultured in a well plate (dish) with no skull/tissue path; fields set to not_reported (rather than null) because the overall study also includes in vivo rat/mouse/swine exposures.