Effect of Peripheral Electrical Stimulation (PES) on Nocturnal Blood Glucose in Type 2 Diabetes: A Randomized Crossover Pilot Study

Abstract

Background: Regulation of hepatic glucose production has been a target for antidiabetic drug development, due to its major contribution to glucose homeostasis. Previous pre-clinical study demonstrated that peripheral electrical stimulation (PES) may stimulate glucose utilization and improve hepatic insulin sensitivity. The aim of the present study was to evaluate safety, tolerability, and the glucose-lowering effect of this approach in patients with type 2 diabetes (T2DM).

Methods: Twelve patients with T2DM were recruited for an open label, interventional, randomized trial. Eleven patients underwent, in a crossover design, an active, and a no-intervention control periods, separated with a two-week washout phase. During the active period, the patients received a daily lower extremity PES treatment (1.33Hz/16Hz burst mode), for 14 days. Study endpoints included changes in glucose levels, number of hypoglycemic episodes, and other potential side effects. Endpoints were analyzed based on continuous glucose meter readings, and laboratory evaluation.

Results: We found that during the active period, the most significant effect was on nocturnal glucose control (P < 0.0004), as well as on pre-meal mean glucose levels (P < 0.02). The mean daily glucose levels were also decreased although it did not reach clinical significance (P = 0.07). A reduction in serum cortisol (P < 0.01) but not in insulin was also detected after 2 weeks of treatment. No adverse events were recorded.

Conclusions: These results indicate that repeated PES treatment, even for a very short duration, can improve blood glucose control, possibly by suppressing hepatic glucose production. This effect may be mediated via hypothalamic-pituitary-adrenal axis modulation.

Trial registration: ClinicalTrials.gov NCT02727790.

Conflict of interest statement

The authors have declared that no competing interests exist.

Figures

Fig 1. CONSORT flow chart and study design.

a. A Crossover design with a two-week washout period separating each trial. b. Summary of study visits and procedures. PES–Home care peripheral electrical stimulation treatment, MGTT–meal glucose tolerance test. In visits V1-V6 and the follow up (FU) visit, all patients underwent a clinical evaluation, and BT (blood tests) were taken. c. PES signal treatment pattern.

Fig 2. Mean interstitial glucose levels averaged over selected time intervals.

24 h, nighttime, and early morning glucose. CONTROL, Glucose average over the two weeks of control period, PES, Glucose average over the second week of PES treatment. Data are means ± SEM

Fig 3. Cortisol levels at the end of the PES and control periods.

a. The cortisol outcome of the two-period crossover trial presented for the CT (n = 6) and TC (n = 5) arms. CT: Control-Treatment arm, TC: Treatment-Control arm. b. Mean Cortisol levels (n = 11), Data are means ± SEM.

Fig 4. Multi-parametric, heat map analysis.

Each column represents a single subject, and the color scale indicates the normalized value of each one of the parameters. The parameters are ordered by hierarchical clustering using the Euclidean distance metric algorithm. Cluster (A) parameters are related to mechanisms that involve HGP pathways, where cluster (B) parameters are more influenced from glucose utilization. More details are found in S2 and S3 Tables.