A single arm trial using passive simulated jogging for blunting acute hyperglycemia

Glycemic fluctuations increase oxidative stress, promote endothelial dysfunction and cardiovascular disease. Reducing glycemic fluctuations is beneficial. We previously reported that a portable motorized passive simulated jogging device, (JD) reduces 24 h glycemic indices in type 2 and non-diabetic subjects. This study evaluates effectiveness and feasibility of JD in blunting large glycemic fluctuation induced by an oral glucose tolerance test (OGTT). The study was performed in 10 adult participants mean age 41.3 ± 13.5 year using interstitial glucose monitor (IG). Each participant fasted for 8 h. followed by an OGTT (Pre-JD), thereafter JD was used for 90 min per day for 7 days, without change to diet or activities of daily living. A repeat OGTT (Post-JD) was performed after completion. The integrated area under the curve (iAUC2h–4h) was computed for the OGTT Pre-JD and Post-JD. Seven days of JD blunted the glucose fluctuation produced by OGTT. JD decreased AUC2h by 17 ± 4.7% and iAUC4h by 15 ± 5.9% (p < 0.03). In healthy mostly obese participants 7 days of JD blunts the hyperglycemic response produced by an OGTT. JD may be an adjunct to current glycemic management, it can be applied in different postures for those who cannot (due to physical or cognitive limitations) or will not exercise. Trial registration: ClinicalTrials.gov NCT03550105 (08-06-2018).

Spontaneous and postprandial fluctuations/spikes of blood glucose that occur in non-diabetic and type 2 diabetic subjects increase oxidative stress and endothelial dysfunction [1][2][3][4][5][6][7][8] . Such spikes promote accelerated development of atherosclerosis leading to coronary artery disease, stroke, peripheral arterial disease and other vascular pathologies [9][10][11] . Additionally, hyperglycemia is an independent predictor of death in many acute settings, including acute myocardial infarction, trauma, head injury, stroke and has been shown to occur in the critical care setting in as many as 68% of the patients [12][13][14] . Therefore, interventions to prevent or minimize these fluctuations should be highly beneficial to health. One such intervention is application of the passive simulated jogging device (Gentle Jogger, Sackner Wellness Products LLC, Miami, FL 33132), a portable, motorized, self-administered, noninvasive movement technology which produces effortless, rapid stepping in place while sitting or lying down. It has been shown to (1) reduce elevated systolic and diastolic blood pressure caused by sitting or lying still 15 , (2) increase short-term heart rate variability 16 and (3) improve 24 h glycemic indices in type 2 diabetic and non-diabetic participants living at home 17 . In 15 healthy women and 11 men, JD increased oxygen consumption about 15% above the resting seated posture and about 13% above the resting supine posture in moderately obese individuals. None receiving JD reached Metabolic Equivalents (METS) that exceeded 1.5 (a threshold for sedentary behavior) 18 . This current study was carried out to quantitatively evaluate the effectiveness of JD in blunting the major glucose fluctuation induced by an oral glucose tolerance test (OGTT).

Materials and methods
Institutional review board approval. This  Passive simulated jogging device (JD). The portable JD incorporates microprocessor controlled, DC motorized rapid movements of foot pedals placed within a plastic chassis to repetitively tap against a semi-rigid surface for simulation of locomotion while the subject is seated or lying in a bed. The device which has been previously described and depicted weighs about 4.5 kg with dimensions of 34 × 35 × 10 cm and can be used in supine or seated postures 15 . Its foot pedals alternate between right and left pedal movements to actively lift the forefeet upward about 2.5 cm followed by active downward tapping against a semi-rigid bumper, simulating feet impacting the ground. Each time the moving foot pedals strike the bumper, a small pulse is added to the circulation as a function of pedal speed. The present study protocol used JD speed of ~ 190 steps in place per min.
Participants. Ten ambulatory individuals without prior history of diabetes who had never taken either insulin or oral diabetic medications were enrolled and gave their informed consent to participate. There were no attempts to modify diet or physical activity, and all participants were told to maintain their normal exercise routine if any. All participants received financial remuneration for their participation. BMI was computed to characterize participants as follows: BMI normal weight 18.5 to 24.9, overweight 25 to 29.9 and obese 30 or more. Demographics are shown in Table 1. Six women and four men constituted the study group. The mean age was 41.3 ± 13.5 year. Using BMI as criteria, three had normal weight, six were overweight, and one was obese.

Study protocol.
On the first day of study, an interstitial continuous glucose monitor (CGM, FreeStyle Libre Pro, Abbott, Alameda, CA), which provides blood glucose values every 15 min, was fixed over the deltoid area on the non-dominant arm. Participants returned 2 days later after an overnight fast, and a baseline oral glucose tolerance test (OGTT-Pre-JD) was performed using Fisherbrand Oral Glucose Drink (75 g) (Thermo Fisher Scientific, Waltham, MA) which they drank within 2 min. Participants were instructed to continue their same diet and physical activity. On day 3 of the study, the participants were taught the operation of JD and requested to use it three times per day for 30 min sessions at 190 pedal steps in place per minute, amounting to greater than 10,000 pedal steps in place per day, for a total of 7 days. To verify compliance with JD use, they were asked to take photographs of the JD monitoring screen at the end of each session daily with a loaned iPhone and to deliver the iPhone to the study coordinator. Participants returned JD after an overnight fast and a second OGTT (OGTT-Post-JD) was administered on the morning of the eighth day. Figure 1 summarizes this protocol.
In a separate study using 5 adult volunteers (3 males and 2 females, age range 50-80 year) we tested whether or not JD can increase nitric oxide (NO) bioavailability using the non-invasive method of downward displacement of the dicrotic notch on the pulse waveform. In brief, descent of the dicrotic notch occurs because NO dilates resistance vessels, thereby delaying pulse wave reflection [19][20][21][22] . The dicrotic notch position is computed from the amplitude of the digital pulse wave (a) divided by the height of the dicrotic notch above the end-diastolic level (b) and designated the a/b ratio. Increase of the a/b ratio due to dicrotic notch descent reflects the vasodilator action of NO on resistance vessels. Thus, release of NO causes downward movement of the dicrotic notch in the diastolic limb of the digital pulse, thereby elevating the a/b ratio 23,24 . Baseline (pre-JD) and 1 to 4 h IG values post ingestion of the glucose beverage were recorded administration and after 7-day treatment with JD. Since these values were not normally distributed, the non-parametric Mann U Whitney test was employed in the statistical analysis (Statistica Software, (Statsoft, TIBCO Software Inc., Palo Alto, CA) Graphs were plotted using GraphPad Prism 8 (GraphPad Software, San Diego, CA). Significant differences between means were taken as p < 0.05. In addition, 2 and 4 h values of each subject's iAUC 2h and iAUC 4h were obtained using all 15 min IG values. In order to gauge the magnitude of effect size of the JD on both iAUC 2h and iAUC 4h , we computed Cohen's d. A value greater than or equal to 0.8 denotes a large effect. The primary endpoint of this study was iAUC. Using a 10% change in iAUC, probability of a type 1 error (α = 0.05) and the probability of a type 2 error (ß = 0.15), a sample size n = 10 would yield a power of 0.85. Data are mean ± standard deviation. Consent for publication. All authors have reviewed the data and manuscript and endorse its conclusion and consent to its publications. Figure 2 depicts IG values over a 4 h period for the OGTT in two representative non-diabetic participants pre and post JD. There is major blunting of the large IG fluctuation associated with glucose ingestion. All ten participants had normal fasting glucose values as measured with CGM, e.g., between 70 and 99 mg/dl both before and after JD administration 25 .

Results
The 1 and 2 h interstitial glucose values pre and post JD for the OGTT are listed in Table 2. Since the 1 h OGTT plasma glucose value as equated with IG greater than 155 mg/dl is predictive of prediabetes 26,27 , 3 of the 10 participants could be considered prediabetes prior to the administration of JD. Following JD treatment for 7 days, 9 of the 10 participants had normal 1 and 2 h glucose values after OGTT administration. One subject had abnormal (158 mg/dl) 1 h glucose (but markedly decreased from pre-JD value (217 mg/dl), and normal (135 mg/dl) 2 h glucose after OGTT post-JD. Figure 3 shows the values for 2 and 4 h mean curves for all subjects and integrated area under the curve (iAUC 2 and 4h ) of the OGTT pre and post JD. Seven days of JD decreased both the 2 and 4 h iAUC by 17% ± 4.7 and 15% ± 5.9 respectively (p < 0.03 and p < 0.002). The effect size of JD on iAUC 2 and 4h was d = 1.01 and d = 1.41 respectively. There was no significant difference in the time to peak glucose for pre and post JD. Peak glucose during Pre-JD occurred at 63 min (range 45-135 min) and Post-JD 67.5 min (range 30-120 min), (p = 0.72).
The effects of JD on NO bioavilabity were determined in seated at rest (baseline) and during JD, using the a/b ratio. Figure 4A,B show the measurement of a/b on a plethysmographic waveform. JD increased a/b ratio by 24-fold from baseline values, confirming that JD increases NO bioavailability in human subjects Fig. 4C.    www.nature.com/scientificreports/  www.nature.com/scientificreports/

Discussion
The current study carried out in normal participants extends previous observations in which JD diminished daily glycemic variability in non-diabetic and diabetic patients 17 . JD reduced OGTT iAUC 2h 17% ± 4.7 in normal participants by suppressing the amplified glycemic fluctuation produced by OGTT. The latter has a physiologically relevant large effect size of Cohen's d = 1.01 28 . JD by producing passive endothelial pulsatile shear stress, like its predicate device, the motion platform (Whole Body Periodic Acceleration (WBPA) aka pGz), and, aerobic exercise increase bioavailability of nitric oxide 23,[29][30][31] . Such activity is also heightened in fidgeting, which consists of tapping 220-290 times a minute compared to ~ 190 taps per minute utilized during operation of JD 32 . It is noteworthy that Flamenco dancers in performance average about 1000 heel taps per minute but no clinical studies on their cardiovascular health or glucose metabolism have yet been undertaken.
In mostly overweight healthy subjects enrolled in the current study, the high glycemic fluctuation produced by ingestion of glucose for the OGTT was significantly dampened by daily JD usage over a 7-day period. The second OGTT was administered at least 8-14 h following the last JD treatment. Compared to baseline, iAUC 2h was reduced by 17% presumably as a result of the action of nitric oxide from upregulation of eNOS and nNOS in skeletal muscle which facilitates blood glucose transport to skeletal muscle [33][34][35] .
Since exercise and WBPA (predicate device of JD) increase bioavailability of nitric oxide by activation of eNOS and nNOS through increased shear stress 23,24,[29][30][31] , the effects of exercise in reported studies of healthy subjects and prediabetic individuals using iAUC 2h from a OGTT after ingestion of 75 g glucose were reviewed for comparison to JD. Such studies included 9-14 normal participants and 26 prediabetics. Daily exercise protocols which were not standardized were performed for 5-14 days and the OGTT obtained 14-24 h following the last exercise procedure for the normal subjects and 8-10 h after the last exercise bout for the prediabetics. In three reports in normal subjects, exercise reduced iAUC 2h 5, 13, and 30% [36][37][38] . In one report of normal subjects and a report of prediabetics, exercise did not change iAUC 2h 39,40 . In a different study 31 healthy normal weight participants were stratified into self-reported physical activity volume and intensity and received and oral glucose tolerance test (50 g glucose). They found a statistically significant decrease in iAUC with increasing level of physical activity (very active > 60 min/day, high intensity group) 41 . Although these data suggest that suppression of large glycemic excursions as produced in a OGTT might be responsive to exercise and JD, clearly more data are needed for a definitive conclusion.
There are limitations to the present study which must be acknowledged. This study was not designed to specifically determine the mechanisms by with JD blunts hyperglycemia, but some useful information can be gleaned from the data. JD increases NO bioavailability, via endothelial derived nitric oxide (eNO). NO derived from eNO, has been shown to increase insulin secretion, improve insulin signaling and sensitivity, increase peripheral glucose uptake, and decrease hepatic glucose output 42 . It is plausible that JD blunts hyperglycemia thru any of these mechanisms. Alternatively, JD could also stimulate passive stretching, the latter has been known to activate muscle glucose uptake through stretch-stimulated glucose uptake, which does not appear to be endothelial nitric oxide synthase (eNOS) or neuronal NOS (nNOS) dependent since passive stretch failed to increase NOS activity above resting levels 43 .
Changes of IG using the FreeStyle Libre Glucose Monitoring System during OGTT in the current trial and plasma glucose values and iAUC were considered equivalent although the absolute values of plasma glucose have been reported about 11% lower than the IG values 44 . Application of CGM during a home trial renders it feasible to use whereas repeated venipunctures for measurements of plasma glucose are impractical. In our initial study of 24 h glycemic variability over 7 days carried out in 11 healthy subjects, %CV was significantly lower between baseline and JD on most days indicating consistency of JD suppressing IG fluctuations during free living 17 . The small sample size in this study precludes us from making population wide generalizable comments, however the sample size in this study is similar to the previously cited studies, and JD induced a significant physiologically effect 34,[37][38][39] . We are also unable to comment on the effects of extended use of JD beyond 7 days, anecdotal data suggests continued effects while JD is utilized in both diabetics and non-diabetics 17 . The latter is relevant since recent large data base analysis of long-term glycemic variability (glycemic fluctuations over months to years) showed that increased long-term glycemic variability is associated with increase cardiovascular disease and mortality in nondiabetics 45 .
The findings of this study are clinically relevant. Hyperglycemia is a common occurrence in the intensive care unit (ICU), is associated with worse outcomes in both adults and children, in both diabetics and non-diabetics, and an independent predictor of in hospital mortality in critically ill patients [12][13][14]46,47 . Further, acute increase in glycemia is accompanied by a large surge of inflammatory mediators, which worsens severity of disease 48 . Therefore, an intervention such as the JD which has been shown to decrease 24 h glycemic indices in diabetics and non-diabetics, and to markedly reduce the large post prandial glucose spike, may be an adjunct in the glycemic control of critically ill patients which requires further studies.

Conclusion
The current trial in healthy mostly overweight participants shows that 7 days of JD significantly blunts the hyperglycemia response produced by an OGTT. JD is a simple to use device which can be used in various postures for those individuals which cannot (due to physical or cognitive limitations) or will not exercise.

Data availability
The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.