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

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.

Abstract via europepmc.

Flags from extraction

• n_subjects — This is a multi-species, multi-experiment paper (chronic/acute glucose studies, clamps, nerve-block studies, electrophysiology, multi-omics, in vitro) with dozens of small, non-overlapping cohorts (n typically 4-20) and no single stated aggregate subject total; left not_reported.
• exposures[0].timing.protocol_description — One sentence describing the ZDF-pFUS protocol gives '150 burst cycles, 500 microsecond burst period', which is hard to reconcile with the system's stated nominal '150 microsecond pulse duration' and '5 Hz pulse repetition frequency'; not entered as a numeric value because the intended quantities are unclear.
• exposures[0].in_situ.ispta_w_cm2 — Two different derated Ispta values are reported for the same 1.1 MHz rodent system: 94.3 +/- 11.2 mW/cm2 from bench characterisation at the nominal 135 mV drive amplitude, and ~581 mW/cm2 'at the ~5 mm target depth in the rats' quoted when describing the swine dose; both are retained as list entries since the paper does not reconcile them (likely different drive amplitudes, given the stated linear MI-vs-amplitude scaling).
• exposures[1].timing.sonication_duration_s — The stimulus duration used during the PVN electrophysiology recording experiments (Fig. 5) is not stated; the 3-min duration used elsewhere is not assumed to apply.
• exposures[3].timing — The in vitro DRG culture experiments reuse the pre-clinical 1.1 MHz hepatic pFUS system, but no pulse duration, PRF, duty cycle or per-trial duration specific to the culture experiments is stated in the text; only the 0.83 MPa peak-positive pressure is given.
• direction_of_effect — Effects on circulating hormones (leptin, GLP-1, ghrelin, norepinephrine) differed in direction between the ZDF and DIO models, and pFUS attenuated but did not reverse the direction of glucose-induced firing-rate changes in hypothalamic glucose-excited neurons; classified as mixed_or_unclear rather than a single direction.