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Abstract

Background:

Exercise-induced muscle soreness and fatigue are significant barriers to physical activity in middle-aged women with type 2 diabetes (T2D), exacerbated by impaired tissue healing and chronic inflammation.

Objectives:

To evaluate whether post-exercise therapeutic ultrasound (TUS) effectively reduces exercise-induced muscle soreness and fatigue while improving metabolic and inflammatory biomarkers in women with T2D.

Design:

Randomized controlled trial.

Methods:

Thirty sedentary women with T2D (aged 41–49 years, glycated hemoglobin (HbA1c) 6.5%–9.0%) were randomized to a TUS group (n = 15) or control (n = 15). Both groups completed an 8-week aerobic cycling program (3 sessions/week, 45 min/session, 60%–70% VO₂max). The TUS group received post-exercise ultrasound (3 MHz, 1 W/cm², 7 min/leg) using the Intellect Mobile 2 device. Primary outcomes were pain (Von Korff scale) and fatigue (Borg scale), while secondary outcomes included fasting blood sugar (FBS), HbA1c, inflammatory markers (tumor necrosis factor-alpha (TNF-α) and interleukin-6 (IL-6)), and creatine kinase (CK), assessed at baseline and post-intervention. Linear mixed-effects models adjusted for baseline pain differences.

Results:

The TUS group showed marked decreases in pain (−2.2, 95% CI: −2.8 to −1.6, p < 0.001) and fatigue (−1.8, 95% CI: −2.4 to −1.2, p = 0.004) compared to controls. Secondary outcomes substantially improved: HbA1c (−0.5%, p = 0.03), FBS (−19.8 mg/dL, p = 0.01), TNF-α (−24.9 pg/mL, p < 0.001), IL-6 (−11.9 pg/mL, p < 0.001), and CK (−30 U/L, p = 0.01). No adverse events were reported.

Conclusion:

TUS is a safe, effective adjunct for reducing exercise-induced muscle soreness and fatigue in women with T2D, with benefits in glycemic control and inflammation. Larger trials with sham controls are needed.

Trial registration:

This trial was registered at the Iranian Registry of Clinical Trials (IRCT20211201053244N1) on June 21, 2022.

Plain language summary

Ultrasound therapy helps reduce muscle pain and fatigue in women with type 2 diabetes after exercise

This study looked at whether ultrasound therapy could help middle-aged women with type 2 diabetes (T2D) feel less muscle pain and fatigue after exercise. Many people with T2D struggle with these issues, which can make it harder to stay active. Staying active is important for managing diabetes, so finding ways to reduce discomfort after exercise could help people stick to their routines.

Thirty women with T2D, aged 41–49, took part in the study. They were divided into two groups: one group received ultrasound therapy on their leg muscles after each exercise session, while the other group simply rested. Both groups did the same cycling exercise three times a week for eight weeks.

The results showed that the women who received ultrasound therapy had significantly less pain and fatigue compared to those who just rested. They also saw improvements in their blood sugar levels and markers of inflammation, which are often high in people with T2D. The therapy was safe, and the women reported feeling satisfied with the treatment.

These findings suggest that ultrasound therapy could be a helpful addition to exercise programs for women with T2D, making it easier for them to recover and stay active. However, more research is needed to confirm these results in larger and more diverse groups of people.

This study highlights a simple, non-invasive way to support exercise recovery and overall health in people with diabetes.

Graphical abstract

Keywords

exercise-induced muscle soreness exercise recovery fatigue glycemic control inflammation randomized controlled trial therapeutic ultrasound type 2 diabetes

Introduction

The worldwide incidence of type 2 diabetes mellitus (T2D) continues to escalate, with an estimated 537 million adults affected in 2021—a figure projected to reach 783 million by 2045, posing a major challenge to healthcare systems worldwide.¹ T2D is defined by chronic insulin resistance, impaired insulin secretion, and persistent low-grade inflammation, which collectively increase the risk of multiple comorbidities, including cardiovascular pathology, neuropathy, nephropathy, and a range of musculoskeletal disorders.^2,3

Middle-aged women with T2D are particularly susceptible to musculoskeletal impairments due to a combination of metabolic dysregulation, age-related hormonal changes—such as declining estrogen levels during perimenopause—and reduced physical activity levels.^4,5 These factors increase the risk of conditions such as osteoarthritis, tendinopathies, and adhesive capsulitis, which contribute to reduced mobility, an elevated risk of falls, and diminished quality of life.⁶ Despite the established benefits of exercise in managing diabetes, physical inactivity remains common in this group, underscoring the need for targeted interventions that support musculoskeletal health and promote sustained physical activity.

Aerobic exercise effectively improves glycemic control and reduces cardiometabolic risk in individuals with T2D.⁷ However, post-exercise muscle soreness and fatigue, which are often more severe and prolonged in this population due to elevated systemic inflammation and impaired muscle repair, can hinder the benefits of regular physical activity. High levels of pro-inflammatory mediators, such as tumor necrosis factor-alpha (TNF-α) and interleukin-6 (IL-6), combined with reduced muscle regenerative capacity, delay recovery after exercise.^8,9 These physiological barriers may worsen insulin resistance, creating a cycle that discourages sustained physical activity, particularly among sedentary, middle-aged women.^10,11

Exercise-induced muscle soreness is frequently cited as a significant deterrent to exercise adherence, with up to 50% of adults with T2D discontinuing exercise programs within 6 months due to discomfort and fatigue.¹² For individuals already facing challenges with muscle recovery and systemic inflammation, the additional burden of soreness may further limit their ability to engage in regular physical activity.

Therapeutic ultrasound (TUS), a non-invasive modality that uses ultrasonic waves to facilitate tissue regeneration and modulate inflammation, has demonstrated benefits in musculoskeletal rehabilitation.^13,14 While TUS is commonly used to treat pain and accelerate soft tissue recovery, its specific application for relieving exercise-induced muscle soreness in individuals with T2D has not been comprehensively studied. Inconsistent findings in healthy adults have been noted in the literature, mainly attributable to variability in protocols and sample traits.¹⁵ Moreover, no randomized controlled trials (RCTs) to date have directly compared the effects of TUS with passive recovery in populations with T2D—despite clear physiological rationale related to their impaired healing, elevated inflammatory markers, and compromised microvascular function.^8,9

While recovery strategies such as cryotherapy and compression therapy have been more widely explored,^15,16 TUS may offer unique benefits due to its deeper tissue penetration and capacity to modulate inflammation at a cellular level.^17,18 These features suggest that TUS could be a valuable adjunct to exercise-based interventions aimed at improving recovery and promoting adherence in this high-risk population.

To address this research gap, the present RCT evaluated the effectiveness of post-exercise TUS in reducing muscle soreness and fatigue among sedentary middle-aged women with T2D. It was hypothesized that TUS would significantly enhance post-exercise recovery and lead to secondary improvements in metabolic outcomes, including fasting blood glucose (FBS) and glycated hemoglobin (HbA1c) levels.¹⁹ This study focused on recurrent exercise-induced soreness and fatigue in women with T2D, who exhibit prolonged recovery due to chronic inflammation and impaired muscle repair.⁸ Unlike acute delayed onset muscle soreness (DOMS), which peaks 24–72 h post-exercise,²⁰ our design targeted cumulative soreness from regular aerobic exercise, a common barrier to adherence in T2D.¹²

Method

Study design

This RCT utilized a parallel-group, single-center design to investigate the impact of TUS on exercise-induced muscle soreness and fatigue in women with T2D. The trial was conducted in Zahedan, Iran, between April and July 2023, adhering to the Declaration of Helsinki and following Consolidated Standards of Reporting Trials (CONSORT) 2010 guidelines for reporting RCTs.²¹ Ethical considerations are detailed in the Declarations section. The study was prospectively registered at the Iranian Registry of Clinical Trials (IRCT20211201053244N1) on June 21, 2022, https://irct.behdasht.gov.ir/trial/64045. No changes were made to the trial methods, including eligibility criteria, intervention protocols, or outcome measures, after trial commencement. All participants provided written informed consent, and confidentiality and safety monitoring were upheld throughout the study.

Participants

Eligible participants were women aged 41–49 years with a confirmed diagnosis of T2D, defined by HbA1c levels between 6.5% and 9.0%. Participants were recruited from a local diabetes clinic, with additional outreach via physician referrals and community advertisements to enhance diversity. Sedentary status was determined based on World Health Organization guidelines, characterized by participation in fewer than 150 min of moderate-intensity exercise weekly.²² All participants were medically cleared to engage in moderate-intensity aerobic exercise.

Exclusion criteria included a history of recent lower-limb exercise-induced muscle soreness, severe peripheral neuropathy (Michigan Neuropathy Screening Instrument score >7), recent cardiovascular events (within 6 months), chronic or recent (within 3 months prior to enrollment) use of analgesics, non-steroidal or steroidal anti-inflammatory drugs, or centrally acting medications (e.g., duloxetine, gabapentinoids), or any contraindications to ultrasound therapy.²³

Interventions

Participants in both groups completed an 8-week supervised aerobic training program using a cycle ergometer (Monark 828E), consisting of three 45-min sessions weekly at an intensity of 60%–70% of estimated maximal oxygen uptake (VO₂max). VO₂max was calculated at baseline via the submaximal Åstrand-Rhyming test, conducted under American College of Sports Medicine protocols.²⁴ Each session included a 5-min warm-up with low-resistance cycling, dynamic stretching, and ended with a 5-min cool-down of slow pedaling and static stretches. Sessions were supervised by licensed physiotherapists, and adherence was tracked via attendance logs and heart rate monitors (Polar H10). Missed sessions were rescheduled within the same week, and participants received weekly motivational check-ins. Participants were monitored for medication changes during the study, and no analgesics, anti-inflammatories, or centrally acting drugs were initiated. Participants were also monitored for lifestyle changes, including diet and unscheduled physical activity, through weekly interviews, although these factors were not systematically recorded.

TUS group

Following each exercise session, participants in the TUS group underwent TUS treatment on the quadriceps femoris muscle. Ultrasound was delivered using the Intellect Mobile 2 device (Chattanooga, DJO Global, Catalog No. 2900), at a frequency of 3 MHz, intensity of 1 W/cm², in continuous mode, for 7 min/leg. The quadriceps femoris muscle, with an estimated depth of 1.5–2.5 cm from the skin surface in our population (based on body mass index (BMI) 28–32 kg/m², measured via clinical palpation and standard anatomical references),²⁵ was targeted using a 3 MHz frequency, which is optimal for penetrating superficial to mid-depth tissues (1–2 cm).²⁵ Under the applied parameters (3 MHz, 1 W/cm²), the estimated acoustic pressure at the target depth (1.5–2.5 cm) is approximately 0.1–0.3 MPa in tissue-mimicking phantoms, based on standard ultrasound physics for soft tissue.^26,27 Continuous 3-MHz ultrasound at 1 W/cm² is estimated to increase muscle temperature by 1°C–3°C over 7 min, based on prior studies in tissue-mimicking phantoms and clinical settings.^25,27 Pilot testing in our study confirmed a skin surface temperature rise of approximately 1°C–3°C, measured via infrared thermometry. A 5-cm² transducer was moved in slow circular motions (approximately 2–3 cm/s) over the anterior quadriceps with Aquasonic 100 ultrasound gel (Parker Laboratories, Inc.) to ensure effective coupling.²⁵ Treatments were administered by physiotherapists with at least 3 years of clinical experience and formal certification in ultrasound therapy.

Control group

Individuals in the control group were provided with passive seated rest for an equivalent duration (7 min/leg) after exercise. This allowed for control over the time and context of recovery without the application of ultrasound.

Intervention fidelity

All physiotherapists underwent standardized training on the TUS protocol to ensure consistent application of frequency, intensity, and transducer movement. To ensure consistency and protocol adherence, all ultrasound sessions were logged with detailed records of frequency, intensity, duration, and treatment site. Weekly audits were performed by a supervising clinician to verify correct application and adherence to treatment parameters.

Outcome measures

Primary outcomes

Primary outcomes encompass self-reported pain and fatigue. Pain was assessed using the Von Korff Chronic Pain Grade scale (0–10), selected for its established validity in assessing pain intensity and its impact on daily functioning (intraclass correlation coefficient (ICC) >0.85), which is particularly relevant for individuals with T2D who may experience chronic musculoskeletal discomfort.¹⁹ This scale was chosen over the Visual Analogue Scale (VAS) because it provides a structured grading system that captures both pain severity and functional impact, reducing subjectivity in a population with chronic conditions. Fatigue was measured via the Borg Rating of Perceived Exertion (6–20).²¹ Pain and fatigue were assessed 24 h post-final session to capture cumulative effects of the 8-week exercise program, given the chronic inflammatory state in T2D that exacerbates recovery.⁹ These were evaluated at baseline and again 24 h after the final exercise session. A change of 1.5–2.0 points on the Borg scale was considered the minimal clinically important difference (MCID) for fatigue.

Secondary outcomes

Secondary measures encompassed markers of glycemic control (HbA1c, FBS), inflammation (TNF-α, IL-6), and muscle damage (creatine kinase (CK)). Blood samples were collected at baseline and post-intervention. TNF-α and IL-6 were quantified using Enzyme-Linked Immunosorbent Assay (ELISA) kits (R&D Systems; TNF-α: DTA00D, R&D Systems), detection limit 0.5 pg/mL; IL-6: (D6050, R&D Systems, Minneapolis, MN, USA), detection limit 0.7 pg/mL), with each sample tested in triplicate. Assay reliability was verified by maintaining intra-assay and inter-assay coefficients of variation below 3% and 5%, respectively. CK levels were measured using spectrophotometric methods,⁸ and FBS was measured after an overnight fast using an Accu-Chek glucometer (Roche Diagnostics, Basel, Switzerland).²⁸

No changes were made to the pre-specified primary or secondary outcome measures after the trial commenced. Outcome assessors were blinded to participant group assignments, and participants were instructed not to reveal their allocation. The integrity of blinding was verified using a post-intervention blinding index. Standardized procedures were used for all assessments, conducted at consistent times across participants. Both the Von Korff and Borg scales demonstrated high reliability (ICC >0.85), and inter-rater agreement among assessors exceeded a kappa coefficient of 0.80 after training.

Sample size calculation

Sample size was estimated using G*Power 3.1 for a repeated-measures analysis of variance (ANOVA), utilizing a medium effect size (f = 0.25) derived from previous TUS studies^28,29 and pilot data indicating a 30% pain reduction. A total of 28 participants (14 per group) provided 80% power to detect a significant group × time interaction at α = 0.05. Accounting for a 10% dropout rate, 30 participants were enrolled.

Randomization, blinding, and safety monitoring

Randomization was performed by an independent statistician using computer-generated permuted blocks (block size = 4) in R version 4.3.1 to ensure allocation concealment. Due to intervention characteristics, blinding of physiotherapists was not possible; nevertheless, participants, outcome assessors, and data analysts remained blinded. The Bang Blinding Index (score = 0.05) confirmed the effectiveness of blinding. Blinding of physiotherapists was not feasible due to the distinct nature of the TUS application compared to passive rest, which required active device operation. Safety was monitored through regular interviews and therapist observations throughout the study. No intervention-related adverse events were reported.

Statistical analyses

Statistical analyses were performed employing SPSS version 24 and R version 4.3.1, with a two-tailed significance threshold set at p < 0.05. Continuous variables were expressed as mean ± standard deviation (SD); variables with non-normal distributions were log-transformed before analysis. Shapiro–Wilk and Levene’s tests were used to evaluate normality and homogeneity, respectively. Variables with non-normal distributions, including CK, were log-transformed before analysis. No interim analyses were conducted, and no stopping rules were applied due to the short duration and fixed sample size of the trial.

Baseline group differences were evaluated using independent t tests for continuous variables and chi-square tests for categorical variables. Linear mixed-effects models (LMMs) implemented in R were used to analyze all outcomes, incorporating fixed effects for treatment group, time points, and their interactions, while accounting for within-subject correlations through random participant intercepts.³⁰ Adjustments were made for baseline HbA1c, BMI, and menopausal status. A sensitivity analysis was conducted by including baseline pain scores as a covariate in the LMMs to account for the 0.7-point difference between groups at baseline. Missing data were addressed using multiple imputations (20 iterations via predictive mean matching), with Little’s Missing Completely at Random (MCAR) test confirming randomness (p = 0.21).

Effects were measured using partial η² (small: 0.01, medium: 0.06, large: 0.14). Tukey’s test was used for post hoc comparisons. Sensitivity analyses included repeated-measures ANOVA (with Greenhouse–Geisser correction if needed) and Wilcoxon signed-rank tests for non-parametric data. Pearson correlations were used to explore relationships between clinical outcomes (e.g., ΔTNF-α vs Δpain) and biomarker changes. No correction for multiple testing was applied due to the exploratory nature of secondary and subgroup analyses. Clinical relevance thresholds—such as ⩾30% pain reduction—were noted, and the number needed to treat (NNT) was determined.

All analyses followed an intention-to-treat approach. The statistical code is available upon request for transparency and reproducibility. Missing data were addressed through multiple imputation to reduce bias and improve robustness. Sensitivity analyses were conducted to assess the impact of missing data handling and model assumptions on the results. Statistical significance was set at an alpha level of 0.05, and 95% confidence intervals were reported for all primary and secondary outcomes.

Results

Participant flow and baseline characteristics

Of the 42 women screened, 30 (71%) qualified for inclusion and were randomly assigned in a 1:1 ratio to undergo TUS therapy (n = 15) or serve as controls (n = 15). Two participants—one from each group—withdrew due to scheduling conflicts, resulting in a final sample of 28 who completed the study (see Supplemental Figure S1 for the CONSORT flow diagram). The trial was completed as planned without early termination or stopping, with all participants followed through the 8-week intervention period.

Baseline demographic and clinical characteristics were similar between groups, confirming successful randomization. Baseline pain scores ranged from 3.0 to 9.0 in the TUS group and 2.0 to 8.0 in the control group, with interquartile ranges of 4.8–7.6 and 4.2–6.8, respectively. No statistically significant differences were observed in age, BMI, HbA1c, FBS, pain, or fatigue levels at baseline (all p > 0.05; Table 1).

Table 1.

Baseline demographic and clinical characteristics of participants by group.

Characteristics	TUS group (n = 15)	Control group (n = 15)	p Value
Age (years)	45.8 ± 3.9	46.2 ± 4.1	0.62
BMI (kg/m²)	27.4 ± 3.2	27.8 ± 3.5	0.54
HbA1c (%)	7.5 ± 0.5	7.6 ± 0.6	0.71
FBS (mg/dL)	140.2 ± 15.3	142.8 ± 14.9	0.62
Pain score (0–10)^a	6.2 ± 2.1	5.5 ± 1.9	0.48
Fatigue (Borg 6–20)^b	14.3 ± 2.4	13.8 ± 2.3	0.56

Values are presented as mean ± standard deviation.

Pain was measured using the Von Korff Chronic Pain Grade scale (0–10).

Fatigue was assessed using the Borg Rating of Perceived Exertion scale (6–20). No statistically significant between-group differences were found at baseline (p > 0.05).

BMI, body mass index; FBS, fasting blood sugar; HbA1c, glycated hemoglobin.

Primary outcome

Pain

LMMs revealed a notable group × time interaction for exercise-induced muscle soreness (F(1, 28) = 14.2, p = 0.001, η² = 0.34). The TUS group exhibited a substantial decrease in Von Korff pain scores from baseline (6.2 ± 2.1) to post-intervention (4.0 ± 1.8; mean change: −2.2, 95% CI: −2.8 to −1.6, p < 0.001). In contrast, the control group exhibited minimal change (baseline: 5.5 ± 1.9; post-intervention: 5.1 ± 1.7; mean change: −0.4, 95% CI: −0.9 to 0.1, p = 0.22). The between-group difference was −1.8 (95% CI: −2.7 to −0.9, p < 0.001). The proportion of TUS participants achieving a clinically meaningful pain improvement (⩾30%) was 80% (12/15) versus 23% (3/13) in the control group, yielding an NNT of 2 (95% CI: 1.14–3.79). NNT confidence intervals were calculated using Altman’s method. The relative risk of achieving a clinically meaningful pain reduction (⩾30%) was 3.48 (95% CI: 1.23–9.84) for the TUS group compared to the control group. To address the 0.7-point baseline pain score difference between groups (p = 0.48), a sensitivity analysis was conducted by including baseline pain scores as a covariate in the LMM. This confirmed the robustness of the findings, with the group × time interaction remaining significant (F(1, 27) = 14.0, p = 0.001, η² = 0.33), indicating that the baseline difference did not influence the results. Post-intervention pain scores are illustrated in Figure 1.

Figure 1.

Pain intensity measured with the Von Korff Chronic Pain Grade scale (0–10) at baseline and Week 8 in women with type 2 diabetes (n = 15 per group). The therapeutic ultrasound (TUS) group showed a significant reduction compared to controls (P = 0.001). Error bars represent standard deviation.

Fatigue reduction

LMMs revealed a significant group × time interaction for fatigue (F(1, 28) = 9.8, p = 0.004, η² = 0.26). The TUS group showed a significant decrease in Borg fatigue scores from baseline (14.3 ± 2.4) to post-intervention (12.5 ± 2.0, p < 0.001, mean reduction: −1.8, 95% CI: −2.4 to −1.2), compared to the control group (baseline: 13.8 ± 2.3, post-intervention: 13.4 ± 2.1, mean reduction: −0.4, p = 0.31, 95% CI: −0.9 to 0.2). The between-group difference was −1.4 (95% CI: −2.0 to −0.8, p = 0.004). The MCID (⩾1.5 points) was achieved by 67% (10/15) of TUS participants versus 15% (2/13) of controls. Fatigue outcomes are depicted in Figure 2.

Figure 2.

Fatigue levels assessed with the Borg Rating of Perceived Exertion scale (6–20) at baseline and Week 8 in women with type 2 diabetes (n = 15 per group). The TUS group exhibited a significant reduction compared to controls (P = 0.002). Error bars represent standard deviation.

Secondary outcomes

Inflammatory and muscle damage markers

Table 2 summarizes biomarker levels at baseline and post-intervention, with within-group and between-group changes. LMMs indicated significant group × time interactions for TNF-α (F(1, 28) = 16.2, p < 0.001, η² = 0.37), IL-6 (F(1, 28) = 12.7, p < 0.001, η² = 0.31), and CK (F(1, 28) = 8.4, p = 0.01, η² = 0.23). The TUS group showed notable decreases in TNF-α (from 85.2 ± 14.8 pg/mL at baseline to 60.3 ± 14.5 pg/mL post-intervention; mean change: −24.9, 95% CI: −32.4 to −17.4, p < 0.001), IL-6 (from 32.1 ± 4.9 pg/mL to 20.2 ± 4.8 pg/mL; mean change: −11.9, 95% CI: −14.1 to −9.7, p < 0.001), and CK (from 150 ± 20 U/L to 120 ± 15 U/L; mean change: −30, 95% CI: −40 to −20, p = 0.01), compared to controls (TNF-α: baseline 84.7 ± 15.3 pg/mL, post-intervention: 80.1 ± 15.2 pg/mL, mean change: −4.6, 95% CI: −12.5 to 3.3, p = 0.12; IL-6: baseline 31.9 ± 5.1 pg/mL, post-intervention: 30.1 ± 5.0 pg/mL, mean change: −1.8, 95% CI: −4.5 to 0.9, p = 0.19; CK: baseline 145 ± 18 U/L, post-intervention: 140 ± 20 U/L, mean change: −5, 95% CI: −14 to 4, p = 0.41). Between-group differences were −20.3 pg/mL (95% CI: −27.8 to −12.8) for TNF-α, −10.1 pg/mL (95% CI: −12.4 to −7.8) for IL-6, and −25 U/L (95% CI: −35 to −15) for CK.

Table 2.

Biomarker levels and changes at baseline and week 8.

Group	Time point	TNF-α (pg/mL)	IL-6 (pg/mL)	HbA1c (%)	FBS (mg/dL)	CK (U/L)
TUS (n = 15)	Baseline	85.2 ± 14.8	32.1 ± 4.9	7.5 ± 0.5	140.2 ± 15.3	150 ± 20
	Week 8	60.3 ± 14.5	20.2 ± 4.8	7.0 ± 0.4	120.4 ± 12.1	120 ± 15
	Δ (95% CI)	−24.9 (−32.4 to −17.4)*	−11.9 (−14.1 to −9.7)*	−0.5 (−0.7 to −0.3)*	−19.8 (−26.1 to −13.5)*	−30 (−40 to −20)*
Control (n = 13)	Baseline	84.7 ± 15.3	31.9 ± 5.1	7.6 ± 0.6	142.8 ± 14.9	145 ± 18
	Week 8	80.1 ± 15.2	30.1 ± 5.0	7.4 ± 0.5	137.5 ± 13.8	140 ± 20
	Δ (95% CI)	−4.6 (−12.5 to 3.3)	−1.8 (−4.5 to 0.9)	−0.2 (−0.4 to 0.0)	−5.3 (−12.4 to 1.8)	−5 (−14 to 4)
Between-group difference (95% CI)		−20.3 (−27.8 to −12.8)	−10.1 (−12.4 to −7.8)	−0.3 (−0.5 to −0.1)	−14.5 (−21.6 to −7.4)	−25 (−35 to −15)

Values are mean ± standard deviation. Δ represents mean change (Week 8 minus Baseline) with 95% confidence intervals. TUS group received therapeutic ultrasound post-exercise; control group rested passively. Statistically significant within-group changes (p < 0.05) are marked with an asterisk (*). All values reflect unadjusted data.

CK, creatine kinase; FBS, fasting blood sugar; HbA1c, glycated hemoglobin; IL-6, interleukin-6; TNF-α, tumor necrosis factor-alpha; TUS, therapeutic ultrasound.

Glycemic control

Significant group × time interactions were observed for HbA1c (F(1, 28) = 6.9, p = 0.03, η² = 0.20) and fasting blood sugar (FBS; F(1, 28) = 7.8, p = 0.01, η² = 0.22). The TUS group showed decreases in HbA1c (from 7.5 ± 0.5% at baseline to 7.0 ± 0.4% post-intervention; mean change: −0.5, 95% CI: −0.7 to −0.3, p = 0.03) and FBS (baseline: 140.2 ± 15.3 mg/dL, post-intervention: 120.4 ± 12.1 mg/dL, mean change: −19.8, 95% CI: −26.1 to −13.5, p = 0.01), compared to controls (HbA1c: baseline 7.6 ± 0.6%, post-intervention: 7.4 ± 0.5%, mean change: −0.2, 95% CI: −0.4 to 0.0, p = 0.45; FBS: baseline 142.8 ± 14.9 mg/dL, post-intervention: 137.5 ± 13.8 mg/dL, mean change: −5.3, 95% CI: −12.4 to 1.8, p = 0.52). Between-group differences were −0.3% (95% CI: −0.5 to −0.1) for HbA1c and −14.5 mg/dL (95% CI: −21.6 to −7.4) for FBS (Table 2).

Exploratory analyses

Correlations

Pearson correlations revealed moderate associations between reductions in pain and inflammatory markers in the TUS group (Δpain vs ΔTNF-α: r = 0.58, p = 0.02; Δpain vs ΔIL-6: r = 0.53, p = 0.03). No significant correlations were observed in the control group (p > 0.05). Pain and fatigue reductions were also correlated with HbA1c improvements in the TUS group (Δpain vs ΔHbA1c: r = 0.49, p = 0.04; Δfatigue vs ΔHbA1c: r = 0.47, p = 0.05). CK reductions were associated with pain relief in the TUS group (r = 0.55, p = 0.03). These associations are summarized in Supplemental Table S1.

Adherence and participant feedback

Participants demonstrated strong adherence to the intervention, attending an average of 85% of scheduled sessions. No intervention-related adverse events were reported. Feedback from TUS group participants indicated high satisfaction, with many perceiving the treatment as beneficial and easy to tolerate (Table 3).

Table 3.

Adherence rates and satisfaction among participants during the 8-week intervention.

Measure	Value
Total participants randomized	30
Participants who completed study	28 (93.3%)
Average adherence (attendance rate)	85% of scheduled sessions
Participant satisfaction (TUS group)	High (perceived benefit; well-tolerated)

Adherence refers to the percentage of scheduled exercise sessions attended. Satisfaction was qualitatively assessed in the TUS group post-intervention via participant surveys.

TUS, therapeutic ultrasound

Menopausal status subgroup analysis

Participants were categorized into pre-, peri-, and post-menopausal groups to examine whether hormonal status influenced treatment response. The TUS group included six pre-menopausal, five peri-menopausal, and four post-menopausal women; the control group had a similar distribution.

LMMs revealed significant three-way interactions (Group × Time × Menopausal Status) for pain (F(2, 28) = 6.4, p = 0.004, ηp² = 0.18) and fatigue (F(2, 28) = 5.7, p = 0.007, ηp² = 0.16). Exploratory subgroup analysis indicated larger pain and fatigue reductions in pre-menopausal women in the TUS group (pain: −2.8, 95% CI: −3.5 to −2.1; fatigue: −2.5, 95% CI: −3.2 to −1.8) compared to peri-menopausal (pain: −2.2, 95% CI: −3.3 to −1.1; fatigue: −1.8, 95% CI: −2.5 to −1.1) and post-menopausal women (pain: −1.8, 95% CI: −2.6 to −1.0; fatigue: −1.2, 95% CI: −1.9 to −0.5). No significant subgroup differences were observed in the control group (p > 0.05). Effect sizes (Cohen’s d) for pain and fatigue reductions in the TUS group were: pre-menopausal (pain: 1.43, 95% CI: 0.29–2.57; fatigue: 1.13, 95% CI: 0.12–2.14), peri-menopausal (pain: 1.13, 95% CI: 0.01–2.25; fatigue: 0.81, 95% CI: −0.31 to 1.93), and post-menopausal (pain: 0.92, 95% CI: −0.30 to 2.14; fatigue: 0.54, 95% CI: −0.58 to 1.66). These subgroup findings are exploratory due to the small sample size per subgroup (n = 4–6) and wide confidence intervals, warranting confirmation in larger studies. These subgroup findings are summarized in Table 4.

Table 4.

Changes in pain and fatigue by menopausal status and group assignment.

Menopausal status	Group	Pain (pre → post)	Δ Pain (95% CI)	Fatigue (pre → post)	Δ Fatigue (95% CI)
Pre-menopausal	TUS	6.4 ± 1.8 → 3.6 ± 1.2	−2.8 (−3.5 to −2.1)	14.5 ± 2.3 → 12.0 ± 1.8	−2.5 (−3.2 to −1.8)
	Control	6.2 ± 1.7 → 6.0 ± 1.6	−0.2 (−1.0 to 0.6)	14.2 ± 2.4 → 14.0 ± 2.3	−0.2 (−1.0 to 0.6)
Peri-menopausal	TUS	6.0 ± 2.0 → 3.8 ± 1.5	−2.2 (−3.3 to −1.1)	14.0 ± 2.2 → 12.2 ± 1.7	−1.8 (−2.5 to −1.1)
	Control	5.8 ± 1.9 → 5.6 ± 1.8	−0.2 (−1.0 to 0.6)	13.8 ± 2.3 → 13.6 ± 2.2	−0.2 (−1.0 to 0.6)
Post-menopausal	TUS	5.8 ± 1.9 → 4.0 ± 1.6	−1.8 (−2.6 to −1.0)	13.8 ± 2.1 → 12.6 ± 1.9	−1.2 (−1.9 to −0.5)
	Control	5.6 ± 1.8 → 5.5 ± 1.7	−0.1 (−0.9 to 0.7)	13.6 ± 2.2 → 13.5 ± 2.1	−0.1 (−0.9 to 0.7)

Values shown as mean ± standard deviation. Δ values represent within-group change scores with 95% confidence intervals. Pain: Von Korff scale (0–10); Fatigue: Borg RPE scale (6–20). Improvements were most pronounced in pre-menopausal participants.

Control, passive rest group; RPE, Rating of Perceived Exertion; TUS, therapeutic ultrasound.

Sensitivity analyses

Multiple imputation for missing data (n = 2) confirmed the robustness of primary and secondary outcome findings (all p < 0.05). Non-parametric Wilcoxon tests for CK yielded consistent results (p = 0.02). Sensitivity analyses excluding participants with baseline HbA1c >8.5% (n = 3) showed no change in significance for pain, fatigue, or biomarkers (all p < 0.05).

Discussion

This RCT demonstrates that TUS effectively reduces exercise-induced muscle soreness and fatigue in middle-aged women with T2D following an 8-week aerobic exercise program, and it also enhances glycemic control and mitigates systemic inflammation. The study’s emphasis on long-term chronic muscle soreness and fatigue, rather than acute DOMS (which typically peaks within 24–72 h after a single intense exercise session), aligns with its experimental design to assess biomechanical and biochemical outcomes.⁸ The 35.5% reduction in pain and significant fatigue decrease observed in the TUS group align with prior studies on ultrasound in musculoskeletal populations,^13,17,22 yet this study is among the first to evaluate these effects specifically in a diabetic cohort—a group known for impaired tissue healing and heightened inflammatory responses.

Crucially, symptom improvements were accompanied by meaningful physiological changes, including a 0.5% decrease in HbA1c, substantial declines in FBS, and reduced levels of TNF-α, IL-6, and CK. The modest reduction in CK likely reflects reduced muscle damage due to TUS, though baseline levels were within normal ranges.^9,15 These findings support the clinical relevance of the intervention and raise the possibility that ultrasound’s benefits may involve anti-inflammatory mechanisms and enhanced muscle recovery.^8,9,17 The absence of adverse events, along with high adherence and participant satisfaction, underscores TUS’s potential as a safe,¹³ acceptable,¹² and feasible adjunct in diabetes rehabilitation.^15,22 To address potential influences on pain outcomes, baseline pain scores, which were 0.7 points lower in the control group, were adjusted for in the statistical analysis using LMMs, ensuring robust results.³¹

The therapeutic benefits of TUS are particularly noteworthy in the context of T2D pathophysiology, which includes reduced microvascular perfusion,¹⁵ chronic low-grade inflammation,^3,9 and delayed muscular repair.⁸ These conditions diminish exercise tolerance and recovery capacity. While previous research has documented TUS effectiveness in managing tendinopathies¹³ and osteoarthritis,^17,22 our findings extend its benefits for post-exercise recovery in a metabolically challenged cohort following long-term exercise. Notably, the effect size observed in pain reduction (η² = 0.34) was larger than or comparable to those reported in meta-analyses of muscle recovery interventions in healthy adults,^16,32 suggesting a potentially greater responsiveness in individuals with T2D.^5,14

The TUS protocol utilized a 3-MHz frequency and 1-W/cm² intensity, applied to the quadriceps femoris muscle, which has an average depth of approximately 1.5–2.5 cm from the skin surface in women of this demographic (BMI 28–32 kg/m²).²⁵ This frequency is suitable for targeting superficial to mid-depth muscles, as 3-MHz ultrasound typically penetrates 1–2 cm effectively, ensuring adequate energy delivery to the quadriceps.²⁵ The acoustic pressure at this depth in tissue-mimicking phantoms is estimated to be approximately 0.1–0.3 MPa under these parameters, sufficient to induce therapeutic effects without excessive tissue heating.²⁶ The modest temperature rise (1°C–3°C) induced by TUS likely contributed to non-thermal effects, such as enhanced microcirculation, rather than significant thermal effects, aligning with prior studies.^15,25,27

The therapeutic effects of TUS primarily arise from non-thermal mechanisms, such as enhanced microcirculation, clearance of metabolic byproducts, and stimulation of satellite cell activation (i.e., activation of muscle stem cells that aid in repair), which together alleviate inflammation and enhance muscle repair.^8,15,25,32 The modest temperature increase (1°C–3°C) indicates minimal thermal effects, with mechanisms such as acoustic streaming (fluid movement caused by ultrasound) and cavitation (microbubble formation) playing a key role in boosting blood flow and reducing chronic inflammation in T2D.^25,27 These processes correspond to the observed decreases in TNF-α and IL-6, which are essential for mitigating insulin resistance and musculoskeletal dysfunction.⁹ For women with T2D, particularly those prone to musculoskeletal issues, these benefits may promote greater participation in physical activity programs.³³ By improving recovery, TUS could lower dropout rates and support long-term exercise adherence, addressing a significant challenge in diabetes management.^12,34

Subgroup analyses suggest that menopausal status may influence response to TUS. Pre-menopausal participants experienced the greatest reductions in exercise-induced muscle soreness and fatigue, which may reflect the modulatory role of estrogen on microvascular function,³ collagen turnover,³⁵ and pain perception.^36,37 While these findings remain exploratory, they open new avenues for investigating how hormonal profiles might interact with physical therapy modalities and recovery interventions.

From a mechanistic standpoint, the reductions in TNF-α and IL-6 are consistent with a systemic anti-inflammatory effect that may contribute not only to improved symptom management but also to better metabolic outcomes. Chronic inflammation is known to exacerbate insulin resistance and musculoskeletal dysfunction in T2D,^5,9 making inflammation-modulating interventions especially valuable. TUS has been shown to enhance microcirculation,¹⁵ stimulate satellite cell activation,⁸ and promote metabolic waste clearance,⁷ all of which may underpin the improved recovery observed in this study. The ELISA kits used for TNF-α and IL-6 had detection limits of 0.5 and 0.7 pg/mL, respectively, ensuring high sensitivity for detecting changes in inflammatory markers. Emerging research on mechanosensitive ion channels, such as Piezo1³⁸ and Piezo2,³⁹ which respond to mechanical stimuli, suggests that ultrasound may exert neuromodulatory effects (i.e., altering neural activity). This offers promising potential for future mechanistic exploration.

Clinically, these findings highlight the practical value of TUS as an accessible, non-invasive modality that can be integrated into exercise programs to help individuals with T2D manage post-exercise muscle soreness and sustain regular physical activity. Since adherence remains a cornerstone of long-term glycemic and cardiovascular management in diabetes,^34,40 recovery-enhancing interventions like TUS may play a pivotal role in optimizing outcomes.¹⁵ Tailoring TUS protocols to individual characteristics, such as menopausal status or baseline inflammation levels, could further enhance its effectiveness.^5,9

Limitations and future directions

This study provides valuable insights but has several limitations. First, it focused on chronic muscle soreness and fatigue from a long-term aerobic exercise program rather than acute soreness, limiting comparisons with studies on single-session exercise. Second, while passive rest as a control helped isolate the physiological effects of TUS, the lack of a sham ultrasound group may introduce placebo-related bias, particularly for subjective outcomes like pain and fatigue. This could have exaggerated the reported improvements in these measures. Third, the study sample was relatively homogeneous, consisting of sedentary women aged 41–49 years with moderately controlled T2D. This limitation affects the generalizability of findings to broader populations, including men, older adults, individuals with poor glycemic control, and those with comorbid conditions. Fourth, the use of the Von Korff scale, while validated for chronic pain, may limit direct comparisons with studies using the VAS, which is more commonly employed for acute pain assessment.¹⁹ The decision was based on the scale’s ability to capture pain intensity and interference in a clinical population with T2D, where chronic musculoskeletal complaints are prevalent.⁵ Future studies could incorporate both scales to enhance comparability. Fifth, the intervention duration was limited to 8 weeks, which constrains the ability to conclude the long-term sustainability of the observed benefits. It remains unclear whether symptom relief and metabolic improvements would persist with continued treatment or after TUS discontinuation. Sixth, the chronic use of analgesics or anti-inflammatory medications was not explicitly excluded, though participants were screened for stable medication regimens to minimize confounding effects. The substantial reduction in TNF-α may be partially attributable to the exercise program or uncontrolled lifestyle factors, such as diet. Lifestyle factors such as diet and non-programmed physical activity were not systematically monitored, which may have influenced biomarker outcomes. Additionally, multiple outcomes and subgroup analyses were conducted, increasing the possibility of type I errors. The exploratory subgroup analysis by menopausal status, while suggestive of differential responses, is limited by the small sample size and wide confidence intervals, necessitating further investigation with larger cohorts. Although statistical corrections and sensitivity analyses were employed, caution is warranted when interpreting secondary and exploratory findings. Finally, the sample size calculation was based on a medium effect size (f = 0.25) derived from prior TUS studies, but the absence of a power analysis specifically tailored to diabetic populations is a limitation.^29,30

We recommend future research: (1) expand sample sizes to enhance statistical power, (2) include more diverse populations to improve generalizability, (3) implement longer intervention durations to assess lasting effects, and (4) incorporate sham ultrasound controls to address placebo effects. Investigating the use of alternative pain scales, such as the VAS, could enhance comparability with other studies.¹⁹ Investigating underlying mechanisms—such as tissue-level changes using imaging or muscle biopsy, and hormonal influences via stratified analysis—may also provide deeper insight into the therapeutic effects of ultrasound. Ultimately, trials that integrate TUS into broader diabetes management programs could help determine its real-world utility and cost-effectiveness.

Conclusion

TUS is a safe, well-tolerated, and effective adjunct to exercise for reducing exercise-induced muscle soreness and fatigue in middle-aged women with T2D. In addition to symptom relief, the intervention produced significant improvements in glycemic control and inflammatory markers, highlighting both clinical and physiological benefits in supporting post-exercise recovery in a population with impaired tissue healing and chronic inflammation. These findings suggest that TUS may enhance diabetes rehabilitation by promoting exercise adherence through improved recovery. Larger trials with extended follow-up, incorporating sham controls and diverse populations, are needed to confirm these benefits and evaluate long-term sustainability before clinical adoption.

Supplemental Material

sj-docx-1-tae-10.1177_20420188251362091 – Supplemental material for Ultrasound therapy for exercise-induced muscle soreness and fatigue relief in women with type 2 diabetes: a randomized controlled trial

Supplemental material, sj-docx-1-tae-10.1177_20420188251362091 for Ultrasound therapy for exercise-induced muscle soreness and fatigue relief in women with type 2 diabetes: a randomized controlled trial by Tahereh Bameri, Mohammadreza Rezaeipour and Javad Nakhzari Khodakheir in Therapeutic Advances in Endocrinology and Metabolism

Supplemental Material

sj-docx-2-tae-10.1177_20420188251362091 – Supplemental material for Ultrasound therapy for exercise-induced muscle soreness and fatigue relief in women with type 2 diabetes: a randomized controlled trial

Supplemental material, sj-docx-2-tae-10.1177_20420188251362091 for Ultrasound therapy for exercise-induced muscle soreness and fatigue relief in women with type 2 diabetes: a randomized controlled trial by Tahereh Bameri, Mohammadreza Rezaeipour and Javad Nakhzari Khodakheir in Therapeutic Advances in Endocrinology and Metabolism

Supplemental Material

sj-docx-3-tae-10.1177_20420188251362091 – Supplemental material for Ultrasound therapy for exercise-induced muscle soreness and fatigue relief in women with type 2 diabetes: a randomized controlled trial

Supplemental material, sj-docx-3-tae-10.1177_20420188251362091 for Ultrasound therapy for exercise-induced muscle soreness and fatigue relief in women with type 2 diabetes: a randomized controlled trial by Tahereh Bameri, Mohammadreza Rezaeipour and Javad Nakhzari Khodakheir in Therapeutic Advances in Endocrinology and Metabolism

Footnotes

Acknowledgements

The authors thank the University of Sistan and Baluchestan for research support, the Zabol Diabetes Clinic for recruitment assistance, and all participants, physiotherapists, and lab staff for their contributions.

Declarations

ORCID iD

Mohammadreza Rezaeipour

Supplemental material

Supplemental material for this article is available online.

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