Effect of focused ultrasound neuromodulation of the superior mesenteric plexus on insulin sensitivity and post-operative hyperglycemia in a swine model of surgical stress

Abstract

Metabolic stress during major surgery increases insulin resistance and causes post-operative hyperglycemia (POHG), which may in turn contribute to post-operative morbidity and mortality. Intensive insulin therapy for POHG is often ineffective and may even worsen patient outcomes. Non-invasive focused ultrasound stimulation (FUS) of glucose-sensing abdominal neurons improves glucose metabolism in animal models of diabetes, but its potential role in treating POHG remains unknown. In this study, we explored whether FUS of the superior mesenteric plexus (SMP) alters insulin sensitivity and post-operative fasting blood glucose (FBG) in a swine model of surgical stress-induced POHG. In each of 3 anesthetized animals, FUS targeting the porta hepatis (PH) of the liver or the SMP was delivered and insulin sensitivity was assessed in each case. In another series of experiments, 4 animals received SMP-FUS and 3 sham stimulation, after which surgical stress was induced via small bowel resection. In the 7 surgically operated animals, insulin sensitivity was measured before and after SMP-FUS (or sham), and fasting blood glucose (FBG) was measured before and 16 h after surgery. In all animals, insulin sensitivity was assessed using the hyperinsulinemic-euglycemic clamp (HEC) method. Results: SMP-FUS elicits a greater increase in insulin sensitivity than PH-FUS. On the day of surgery, SMP-FUS increases insulin sensitivity, compared to sham treatment. The day after surgery, surgically operated animals develop mild hyperglycemia. SMP-FUS-treated animals have higher FBG than sham-FUS-treated animals. No clear relationship is observed between FUS-induced changes in insulin sensitivity and next-day FBG. Conclusion: While SMP-FUS improves insulin sensitivity during surgery, it may exacerbate POHG.

Keywords: Focused ultrasound stimulation; Neuromodulation; Post-operative hyperglycemia; Superior mesenteric plexus.

Fig. 1

Experimental procedures and timeline. A) Example of hyperinsulinemic-euglycemic clamp procedure (HEC). Insulin is infused at a constant rate throughout the procedure, while the glucose infusion rate (GIR) is adjusted to maintain blood glucose levels at a predefined target within 30 min, at which time a “clamp” is established. Afterwards, FUS is delivered to the target site (PH or SMP), and the GIR is readjusted to maintain glucose levels at the clamped level. (B) Ultrasound imaging showing that stimulation targeted the SMP located near the superior mesenteric artery (SMA). (C) Timeline of the testing protocol in the swine model of surgical stress, in which FUS (or sham) was delivered to the SMP for 30 min, before the surgical procedure was initiated

Fig. 2

Direct effect of FUS (30 min; 55% maximum intensity), applied either on PH (A) or SMP (B) on insulin sensitivity assessed through a HEC procedure. Shown separately are traces of % changes of glucose concentrations (top) and traces of GIR (bottom), before, and after FUS in individual animals (n = 3)

Fig. 3

Direct effects of SMP-FUS and sham stimulation on insulin sensitivity, in animals that subsequently underwent surgical stress. (A) Blood glucose levels (top panel) and glucose infusion rates (GIR, bottom panel) in 4 animals, before, during and after 30 min of SMP-FUS, under conditions of HEC. Each colored trace represents a different animal. (B) GIR before and after FUS, during HEC. (C) Same as (A), but for animals in which sham stimulation was delivered. (D) GIR before and after sham stimulation, during HEC

Fig. 4

Next-day glycemic response in animals that underwent surgical stress, after either SMP-FUS or SMP-sham stimulation. (A) Fasting blood glucose on the day before and on the day after surgery for each animal that received FUS (rank-sum, *p < 0.05). (B) Same as (A), but for animals that received sham stimulation (rank-sum, p = ns)