Effects of pioglitazone with and without exercise training on cardiorespiratory fitness and oxygen uptake kinetics in type 2 diabetes

Abstract

Aims

Exercise tolerance is often impaired in type 2 diabetes (T2D), and barriers to regular exercise are common. This study evaluated whether 12 weeks of pioglitazone (PIO) therapy could enhance peak oxygen uptake (V̇O_2peak) and the time constant of the primary phase of oxygen uptake (τV̇O_2p) during submaximal exercise, compared with exercise training, and whether combining PIO with exercise would provide additional benefits in T2D.

Materials and Methods

Male participants with T2D were assigned to one of the following groups: (1) non‐exercising control (CON, n = 12), (2) PIO (15 mg/day) alone (PIO, n = 6), (3) exercise training alone (EXC, n = 13), or (4) PIO combined with exercise (PIO + EXC, n = 7). Exercise involved aerobic and resistance training three times per week for 12 weeks. V̇O_2peak (incremental cycling) and τV̇O_2p, mean arterial pressure, and cardiac output (inert gas re‐breathing) during cycling were assessed pre‐ and post‐intervention.

Results

PIO and PIO + EXC groups showed reductions (p < 0.01) in glycated haemoglobin (HbA_1c). V̇O_2peak increased (p < 0.05) and τV̇O_2p decreased (p < 0.01) in both the EXC (V̇O_2peak: 2.44 ± 0.38 to 2.73 ± 0.42 L·min⁻¹; τV̇O_2p: 42.7 ± 6.2 to 34.3 ± 7.2 s) and PIO + EXC (V̇O_2peak: 2.66 ± 0.43 to 2.88 ± 0.42 L·min⁻¹; τV̇O_2p: 40.3 ± 10.6 to 32.7 ± 8.3 s) groups. The magnitude of these effects was not different between the exercising groups. PIO alone did not induce changes in V̇O_2peak or τV̇O_2p. Neither exercise nor PIO altered systemic cardiovascular dynamics.

Conclusions

Although PO improved glycaemic control, it did not enhance aerobic exercise capacity or V̇O₂ kinetics. Moreover, in combination with exercise training, PIO did not provide additional benefits beyond those achieved through exercise alone.

1. INTRODUCTION

Type 2 diabetes (T2D) affects over 400 million people globally, with cases rising due to ageing, sedentary lifestyles and obesity. Exercise is typically recommended at diagnosis for its benefits in slowing disease progression and reducing cardiovascular risk. ¹ However, fewer than 40% of people with T2D engage in regular physical activity, ² and many do not reach the intensity needed for significant improvements in glycaemic control. ² , ³ One potential barrier to regular exercise is an underlying exercise impairment, even among individuals free from overt microvascular complications. Compared with healthy counterparts, individuals with T2D experience greater physiological strain during physical activity, ⁴ making exercise more challenging and possibly discouraging adherence. Peak oxygen uptake (V̇O_2peak) is consistently reduced across all age groups, ⁵ , ⁶ , ⁷ , ⁸ , ⁹ and in those under 60 years of age, V̇O₂ kinetics during moderate‐ and heavy‐intensity exercise are also impaired (i.e., slowed), as indicated by a prolonged time constant of the primary phase of the V̇O₂ response (τV̇O_2p). ⁵ , ⁶ , ⁷ , ¹⁰ , ¹¹ , ¹² These impairments carry important clinical implications. V̇O_2peak strongly predicts cardiovascular and all‐cause mortality, ¹ while τV̇O_2p is a key indicator of exercise tolerance. ¹³ , ¹⁴ Slower V̇O₂ kinetics increase the oxygen deficit at exercise onset, heightening the reliance on substrate‐level phosphorylation and contributing to early fatigue. ¹⁵ Contributing mechanisms include reduced left ventricular filling, ¹⁶ , ¹⁷ impaired peripheral vasodilation and microvascular function, ⁵ , ¹⁰ , ¹¹ , ¹⁸ , ¹⁹ , ²⁰ , ²¹ , ²² and restricted muscular oxygen extraction. ²³

Exercise interventions lasting 3–12 weeks, involving aerobic and/or concurrent exercise, can significantly improve cardiorespiratory fitness in T2D by increasing V̇O_2peak by ~15%–20% ²⁴ , ²⁵ , ²⁶ , ²⁷ and accelerating τV̇O_2p by ~25%–30% during moderate and high‐intensity submaximal exercise. ²⁴ , ²⁷ , ²⁸ , ²⁹ , ³⁰ However, due to barriers to exercise adherence in this cohort, ³¹ there is clinical interest in pharmacological alternatives to mimic these benefits. One such candidate is pioglitazone (PIO), a commonly prescribed ³² insulin‐sensitizing agent belonging to the thiazolidinedione (TZD) class, which acts via peroxisome proliferator‐activated receptor gamma (PPARγ) activation. Treatment with PIO has been shown to improve V̇O_2peak in individuals with metabolic syndrome, ³³ and enhance cardiac function in individuals with T2D without cardiovascular disease, with effects similar to exercise training. ³⁴ Nevertheless, it is unknown whether PIO alone can improve aerobic capacity and/or V̇O₂ kinetics in T2D, or whether combining PIO with exercise yields additive or synergistic benefits.

Accordingly, the present study aimed to determine whether PIO treatment alone improves V̇O_2peak and V̇O₂ kinetics in individuals with T2D, and whether combining PIO with exercise training results in synergistic enhancements in these parameters. To explore if potential improvements in V̇O₂ kinetics were linked to central cardiovascular adaptations and enhanced oxygen delivery, cardiac output measurements were obtained during submaximal exercise. It was hypothesised that PIO would enhance peak aerobic capacity and V̇O₂ kinetics in T2D, and that combining PIO with exercise training would result in further improvements in these outcomes.

2. MATERIALS AND METHODS

2.1. Design and participants

This is the primary study within a broader investigation assessing sex ³⁰ and age‐related differences in how exercise training impacts peak oxygen uptake (V̇O_2peak) and metabolic and cardiovascular responses during submaximal exercise in individuals with T2D, independently of PIO therapy. Participants were non‐randomly allocated to either a 12‐week supervised exercise training programme or a control group that did not exercise. Both groups included subsets receiving PIO, for the evaluation of the drug's specific effects on exercise tolerance and V̇O₂ kinetics. Participants were recruited from outpatient clinics at St. Columcille's and St. Vincent's University Hospitals in Dublin. Eligibility criteria included a clinical diagnosis of T2D of less than 10 years and HbA_1c levels below 10%. Individuals using thiazolidinediones or insulin, smokers, those contraindicated for exercise, or those with BMI > 40 kg/m² or significant organ disease were excluded (Table 1).

TABLE 1.

Participants' clinical characteristics and activity levels at baseline and changes in physical characteristics and GXT variables before and after the 12‐week intervention in male participants with type 2 diabetes.

	Pre/post intervention	CON (n = 12)	PIO (n = 6)	EXC (n = 13)	PIO + EXC (n = 7)
Clinical characteristics and activity levels
Age (years)		57.3 ± 10.2	57.3 ± 11.2	60.7 ± 5.8	54.6 ± 3.8
Time since diabetes diagnosis (years)		3.9 ± 2.4	3.9 ± 2.5	4.2 ± 2.6	3.7 ± 3.2
Diabetes medication
Diet only, n (%)		3 (25)	2 (33)	4 (31)	4 (57)
Metformin, n (%)		7 (58)	3 (50)	5 (38)	2 (29)
Sulfonylurea, n (%)		2 (17)	1 (17)	4 (31)	3 (43)
Antihypertensive medication, n (%)		7 (58)	4 (67)	8 (62)	2 (29)
Statins, n (%)		7 (58)	4 (67)	9 (69)	2 (29)
Habitual physical activity
LPA, h/day		5.2 ± 1.4	4.9 ± 1.3	4.2 ± 0.9	5.2 ± 1.1
MVPA, h/day		1.1 ± 0.4	1.3 ± 0.5	1.1 ± 0.6	1.0 ± 0.7
Changes in physical characteristics and GXT variables
Body mass (kg) b	Pre	94.5 ± 10.8	97.1 ± 14.8	91.6 ± 11.8	93.2 ± 16.0
	Post	94.5 ± 11.2	99.0 ± 15.0	92.0 ± 11.2	94.0 ± 17.0
BMI (kg m−2) b	Pre	30.5 ± 3.7	31.3 ± 3.9	29.6 ± 2.3	31.4 ± 5.3
	Post	30.7 ± 3.6	32.1 ± 4.2	29.9 ± 2.3	31.7 ± 5.8
HbA1c (%) b , c	Pre	6.4 ± 0.5	6.8 ± 0.6	6.9 ± 1.2	6.9 ± 0.8
	Post	6.5 ± 0.5	6.4 ± 0.4 a	6.9 ± 1.2	6.6 ± 0.7 a
Glucose (mM)	Pre	7.02 ± 1.11	7.34 ± 0.48	7.50 ± 1.80	7.79 ± 1.01
	Post	7.75 ± 1.74	7.16 ± 0.67	7.64 ± 2.47	7.49 ± 1.22
V̇O2peak (L min−1) b , c	Pre	2.49 ± 0.35	2.54 ± 0.60	2.44 ± 0.38	2.66 ± 0.43
	Post	2.44 ± 0.49	2.65 ± 0.61	2.73 ± 0.42 a	2.88 ± 0.42 a
V̇O2peak (mL min−1 kg−1) b , c	Pre	26.6 ± 4.3	26.1 ± 4.2	26.8 ± 4.2	28.8 ± 4.6
	Post	26.0 ± 5.4	26.9 ± 5.9	29.8 ± 4.0 a	31.0 ± 4.3 a
POpeak (W) b , c	Pre	157 ± 24	159 ± 29	162 ± 29	164 ± 29
	Post	155 ± 29	164 ± 35	189 ± 36 a	191 ± 37 a
HRpeak (beat min−1)	Pre	151 ± 17	154 ± 25	153 ± 18	156 ± 11
	Post	151 ± 21	154 ± 24	154 ± 19	154 ± 11
GET (W) b , c	Pre	125 ± 22	135 ± 22	128 ± 23	139 ± 23
	Post	128 ± 24	135 ± 30	155 ± 30 a	164 ± 27 a
O2 pulse (mL beat−1) b , c	Pre	16.5 ± 1.9	16.8 ± 4.1	16.1 ± 2.6	17.2 ± 3.4
	Post	16.1 ± 2.1	17.4 ± 4.1	17.9 ± 2.5 a	18.8 ± 3.2 a

Note: Data are mean ± SD; n number of participants.

Abbreviations: BMI, body mass index; CON, control; EXC, exercise; GET, gas exchange threshold; HbA_1c, glycated haemoglobin; HR, heart rate; LPA, light‐intensity physical activity; MVPA, moderate‐to‐vigorous physical activity; PIO, pioglitazone; PO, power output; V̇O₂, oxygen consumption.

^a Significantly different from pre‐training within the same group (p < 0.05).

^b Significant main effect of time (p < 0.05).

^c Significant time × group interaction (p < 0.05).

From the initial 280 eligible patients identified through medical chart review, 40 patients expressed interest. They completed a treadmill ECG stress test and were non‐randomly assigned into four groups: (1) control (CON, initially n = 13), (2) PIO (15 g/day) only (PIO, initially n = 4), (3) exercise only (EXS, initially n = 15) and (4) PIO plus exercise (PIO + EXC, initially n = 8). Non‐random assignment was mainly due to the fact that some participants could not easily attend the location where exercise training was carried out. Six participants later dropped out for unrelated personal reasons (CON, n = 1; PIO, n = 2; EXS, n = 2; PIO + EXC, n = 1). Participants in the control group were offered re‐allocation after the 12 weeks, and four participants later crossed over to PIO treatment. Ultimately, 34 participants completed the intervention, with 38 complete datasets included for statistical analysis across the groups: CON (n = 12), PIO (n = 6), EXS (n = 13), and PIO + EXC (n = 7) (Figure S1). This approach has been employed in similar exercise training interventions in T2D. ²⁵ , ²⁶ All participants provided written consent, and the study received ethical approval from Trinity College Dublin (Ref: 131003) and St. Vincent's Healthcare. The study was conducted in accordance with the principles outlined in the Declaration of Helsinki. Compliance with PIO dosing was assessed through weekly phone calls from study investigators.

2.2. Exercise training intervention

Training consisted of up to 36 sessions over 12 weeks (three sessions per week), with compliance defined as attending at least 32 sessions. Sessions were supervised by study researchers with combined aerobic and resistance (i.e., concurrent) training prescribed given that combined modalities elicit greater reductions in HbA_1c in T2D than either alone. ³⁵ A detailed description of each training phase is shown in Table 2. Briefly, each session lasted 60–90 min and included 5 phases: (1) Continuous cycling: 20–25 min at 70%–80% HR_peak; (2) Flexibility exercises: targeted upper and lower body stretching; (3) Core strengthening: sit‐ups, planks and back extensions with 20–30 reps each; (4) Resistance training: upper (bench press, upright row, shoulder press, and lateral pull down) and lower limb exercises (leg extension, leg curl and leg press) at 60%–70% one‐repetition maximum for two sets of 10 reps; and (5) High‐intensity interval exercise: up to three 90–120 s efforts at 90% HR_peak, using a machine of the participant's choice, with two‐minute rest periods. Training intensity and/or duration was increased after 4 and 8 weeks to promote progression.

TABLE 2.

Summary of the 12 week supervised exercise intervention training at a frequency of 3 times per week.

Component	Mode	Duration and intensity	Progression
			Weeks 1–4	Weeks 5–8	Weeks 9–12
1. Aerobic I (Continuous)	Cycling	20–25 min (incl. warm‐up) at 70%–80% HRpeak	20 min at 70% HRpeak	25 min at 75% HRpeak	25 min at 80% HRpeak
2. Flexibility	Static (upper and lower body)	5–10 min	Hold static stretch 10–15 s	Hold static stretch 15–30 s	Hold static stretch 15–30 s
3. Core strengthening	Bodyweight	5–10 min	20 reps each	30 reps each	30 reps each
4. Resistance training	Compound machines (upper and lower body)	10–20 min, 4–7 exercises, 2 sets of 10 reps at 60%–70% 1‐RM	2 sets of 10 reps at 60% 1‐RM. Day 1: upper body Day 2: lower body Day 3: full body	2 sets of 10 reps at 70% 1‐RM (reassessed). Full body	2 sets of 10 reps at 70% 1‐RM (reassessed). Full body
5. Aerobic II (HIIE)	Mode of choice: cycling, walking, running, elliptical or rowing	20–25 min of HIIE (incl. cool down)	20 min at 70% HRpeak	20 min (3 × 90 s at 75%–85% HRpeak with 2 min rest)	25 min (3 × 2‐min at 75%–85% HRpeak with 2 min rest)

Note: Specific components and progression of the 12‐week supervised exercise intervention.

Abbreviations: HIIE, high‐intensity interval exercise; HR, heart rate; RM, repetition maximum.

2.3. Testing

Participants underwent laboratory testing on two separate days, both before and after the 12‐week intervention at the same time of day, and separated by 72 h. On the first day, they completed a graded exercise test (GXT) to exhaustion on a cycle ergometer. This test began at 40 W, with the workload increasing by 30 W every 3 min until the participant could no longer maintain the required cadence. ³⁶ The gas exchange threshold (GET) was determined using the V‐slope method, ³⁷ peak responses (including V̇O₂) were the highest 30‐s mean values recorded, and peak workload was calculated as described elsewhere. ³⁸ On the second day, participants performed six submaximal cycling bouts. Each bout began with 3 min of ‘unloaded’ cycling at 10 W, followed by 6 min at an intensity equivalent to 80% of their individually determined GET. After the training intervention, the bout intensities were recalculated to match any changes in power output at GET so that the relative intensity of exercise was the same before and after the intervention (i.e. 80% GET). Twelve‐minute rest intervals separated the six bouts to ensure that baseline HR (n = 38) and blood lactate (measured in a subgroup, n = 25) remained stable prior to each bout. During the first four bouts, V̇O₂ and HR were recorded continuously, while during the last two bouts, cardiac output (CO) and mean arterial pressure (MAP) were measured. Parameter estimates for V̇O₂ kinetics appear to be not different whether multiple bouts are performed in one day or spread across several days. ³⁹ Venous blood samples were collected following a 12‐h overnight fast 24–48 h before exercise tests were performed, and participants were instructed to abstain from caffeine and alcohol for 24 h before each testing session.

2.4. Measurements

Pulmonary gas exchange was assessed breath‐by‐breath using a system (Innocor, Innovision A/S, Odense, Denmark) which measured expired air flow and respiratory gases sampled at the mouthport. This system computed V̇O₂, rate of CO₂ output (V̇CO₂), minute ventilation (V̇_E) and respiratory exchange ratio (RER). CO was measured using the same system but with the re‐breathing of an inert gas mixture (sulphur hexafluoride and nitrous oxide). Cardiac output measurements were restricted to rest, 30 s, and 240 s of exercise because of the time required for adequate re‐breathing and measurement. ⁵ , ⁴⁰ Heart rate was recorded every 5 s (S610i, Polar Electro Oy, Finland). Stroke volume (SV) was calculated from simultaneous HR and CO measurements. Mean arterial pressure (MAP) was estimated from sphygmomanometric measurements of brachial arterial pressures (0.33 systolic +0.66 diastolic) performed at the same times CO was measured. Systemic vascular conductance (SVC) was calculated from CO and MAP measurements (SVC = CO/MAP). All cardiovascular measurements were mean values of responses during two exercise bouts. The key measurement variables obtained during the intervention are summarised in Table S1.

2.5. Analysis of kinetic responses of V̇O₂ and cardiovascular variables

The analysis of V̇O₂ kinetics focused on data obtained from the first four submaximal exercise bouts performed at a relative intensity (80% GET) before and after training. Baseline V̇O₂ was established by averaging the values recorded during the final 60 s of unloaded cycling prior to the workload transition. Data collected between 0 and 240 s after the transition were interpolated to one‐second intervals, time‐aligned, averaged across bouts and smoothed using a five‐second moving average. These processed data were then fitted to either a monoexponential (Equation 1) or a biexponential (Equation 2) model depending on the response profile. A monoexponential function was applied to the majority of responses (82%), capturing the primary phase of V̇O₂ adjustment. In cases where a clear second slow phase was observed (18% of cases; mean ± SD amplitude: 104 ± 70 mL min⁻¹), a biexponential model was used. The equations are:

$$\mathrm{V}\dot{}{\mathrm{O}}_2\left(t\right)=a+A_1·\left(1–e^{–\left(\left(t–\text{TD1}\right)/\tau 1\right)}\right)·F_1$$ (1)

$$\mathrm{V}\dot{}{\mathrm{O}}_2\left(t\right)=a+A_1·\left(1–e^{–\left(\left(t–\mathrm{TD}1\right)/\text{τ1}\right)}\right)·F_1+A_2·\left(1–e^{–\left(\left(t–\text{TD2}\right)/\tau 2\right)}\right)·F_2$$ (2)

where a is baseline V̇O₂ at 10 W, A ₁ and A ₂ are amplitudes of the primary and slow phases, τ ₁ and τ ₂ are their respective time constants, and TD₁ and TD₂ are the corresponding time delays. Conditional expressions F ₁ and F ₂ ensure that each phase is fitted only after its time delay. Although the first 20 seconds of data (to avoid the ‘cardiodynamic phase’) were excluded, TD₁ was allowed to vary during fitting to improve parameter estimation. The'primary' V̇O₂ phase, particularly the time constant of this phase (τ ₁ = ‘τ _p V̇O₂’) is most affected by T2D, so only these estimates and derived values are presented. Data were fitted using a two‐step weighted least‐squares non‐linear regression, with outliers removed after the first step. The V̇O₂ gain (A ₁/Δpower) and end‐exercise V̇O₂ (mean V̇O₂ during last 30 s) were calculated.

Dynamic responses of CO, SV, MAP, SVC and HR were estimated from averaged responses measured during the last two of six exercise bouts. Dynamic responses of these variables were estimated by expressing their changes over the initial 30 s of exercise as percentages of changes over 240 s (Δ30/Δ240 × 100%).

2.6. Statistical analyses

Age, diabetes duration and physical activity levels as well as baseline physical characteristics and values of all GXT variables were compared using a one‐factor ANOVA. Changes in physical characteristics, peak physiological responses, kinetics parameter estimates of V̇O₂ and cardiovascular dynamic parameters were compared using a two‐factor mixed ANOVA [time (pre‐training, post‐training) versus group (CON, PIO, EXC, PIO + EXC)]. Differences between groups were identified using Bonferroni's post hoc test. The magnitude of the intervention‐induced changes in selected variables between the exercising groups or between the PIO groups was analysed using a t test. The level of significance was set at p < 0.05. Values are expressed as mean and SD.

3. RESULTS

3.1. Participant characteristics and GXT variables

Participant characteristics and GXT responses are shown in Table 1, while Figure 1 illustrates individual and mean group responses of V̇O_2peak. Participants from the PIO and PIO + EXC groups showed 100% compliance with PIO dosing. Compliance to training in exercising groups (EXC, PIO + EXC) was high, with an average of 35.0 (range, 32–36) out of a maximum of 36 training sessions. Participants' age, time since diabetes diagnosis, or activity levels were not different between groups (for all variables, p > 0.21). Similarly, baseline physical characteristics and variables from the GXT did not differ between groups (for all variables, p > 0.55). There was a significant main effect of time (pre‐ vs. post‐training) for body mass and BMI (p = 0.005 and p = 0.004), with weight gains primarily observed in the PIO group. However, the interaction term did not reach significance (time × group: p = 0.087, p = 0.077). For HbA_1c, a significant time × group interaction was found (p = 0.007), with post‐intervention values being lower than pre‐intervention values only in both groups treated with PIO. The magnitude of the reduction was not significantly different between the PIO and PIO + EXC groups (t tests, p = 0.44). Absolute and relative V̇O_2peak, PO_peak, O₂ pulse, and PO at GET were all significantly higher post‐intervention compared with pre‐intervention only in both exercise groups (significant time × group interaction for all values, p < 0.003). The magnitude of these improvements, both in absolute and percentage terms, did not differ between the EXC and PIO + EXC groups (t tests for all values, p > 0.1).

FIGURE 1.

Individual and mean responses of V̇O_2peak in the four experimental groups before and after the 12‐week intervention. *Significantly different from pre‐training within the same group (p < 0.05).

3.2. VO ₂ kinetics

Table 3 presents parameter estimates and derived measurements related to V̇O₂ kinetics (primary phase), along with statistical outcomes. The time constant of V̇O₂ (τV̇O_2p) was lower (i.e., faster) post‐training compared with pre‐training only in both exercise groups (significant time × group interaction, p < 0.001). The magnitude of improvement in τV̇O_2p, both in absolute and percentage terms, was not significantly different between the EXC and PIO + EXC groups (t tests for all values, p > 0.74). A main effect of time was found for the V̇O₂ primary amplitude and end‐exercise V̇O₂ (p = 0.008 and p = 0.010). While these effects were driven by increases in the exercise groups, there was no significant time × group interaction (p = 0.085, p = 0.26).

TABLE 3.

V̇O₂ kinetics parameters and changes in cardiovascular variables during submaximal exercise before and after a 12‐week intervention in male participants with type 2 diabetes.

	Pre/post intervention	CON (n = 12)	PIO (n = 6)	EXC (n = 13)	PIO + EXC (n = 7)
V̇O2 kinetics parameters
V̇O2 base (L min−1)	Pre	0.77 ± 0.12	0.83 ± 0.12	0.80 ± 0.13	0.82 ± 0.21
	Post	0.77 ± 0.13	0.83 ± 0.12	0.81 ± 0.13	0.82 ± 0.15
τ p V̇O2 (s) b , c	Pre	41.6 ± 9.8	41.3 ± 9.6	42.7 ± 6.2	40.3 ± 10.6
	Post	42.9 ± 7.6	43.1 ± 11.6	34.3 ± 7.2 a	32.7 ± 8.3 a
V̇O2 TD (s)	Pre	19.1 ± 5.0	17.4 ± 8.9	16.2 ± 11.1	21.1 ± 0.9
	Post	15.5 ± 7.7	21.5 ± 12.1	16.6 ± 4.5	22.7 ± 6.7
V̇O2 Amp (L min−1) b	Pre	0.93 ± 0.23	1.02 ± 0.23	1.00 ± 0.28	1.08 ± 0.24
	Post	0.97 ± 0.21	1.01 ± 0.25	1.21 ± 0.30	1.19 ± 0.16
V̇O2 Gain (mL min−1 W−1)	Pre	10.3 ± 1.2	10.2 ± 1.1	11.1 ± 3.2	11.9 ± 0.16
	Post	10.6 ± 1.1	10.8 ± 1.4	10.5 ± 1.1	10.3 ± 1.5
End V̇O2 (L min−1) b	Pre	1.75 ± 0.23	1.85 ± 0.21	1.81 ± 0.26	1.90 ± 0.38
	Post	1.81 ± 0.32	1.89 ± 0.35	2.07 ± 0.34	2.05 ± 0.25
Dynamic changes in cardiovascular variables
ΔCO30/ΔCO240 (%)	Pre	75 ± 10	66 ± 17	69 ± 11	65 ± 14
	Post	73 ± 11	63 ± 13	74 ± 6	67 ± 9
ΔHR30/ΔHR240 (%) b	Pre	54 ± 9	46 ± 7	49 ± 16	53 ± 15
	Post	45 ± 12 a	56 ± 18	45 ± 12	52 ± 16
ΔSV30/ΔSV240 (%)	Pre	110 ± 27	104 ± 49	94 ± 26	89 ± 28
	Post	114 ± 26	82 ± 28	106 ± 16	99 ± 35
ΔMAP30/ΔMAP240 (%)	Pre	64 ± 22	69 ± 12	72 ± 17	70 ± 13
	Post	78 ± 10	75 ± 12	71 ± 18	68 ± 13
ΔSVC30/ΔSVC240 (%)	Pre	83 ± 17	68 ± 31	72 ± 13	68 ± 22
	Post	76 ± 14	64 ± 13	78 ± 9	72 ± 15

Note: Data are mean ± SD. Cardiovascular responses over 30 s are expressed as percentages of responses over 240 s of exercise (i.e. change from rest) to provide estimates of the dynamic responses of these variables during exercise.

Abbreviations: Amp, amplitude; base, baseline; CO, cardiac output; End; end‐exercise; GET, gas exchange threshold; HR, heart rate; MAP, mean arterial pressure; SV, stroke volume; SVC, systemic vascular conductance; TD, time delay; τ _p V̇O₂, time constant of V̇O₂ during the primary phase.

^a Significantly different from pre‐training within the same group (p < 0.05).

^b Significant main effect of time (p < 0.05).

^c Significant time × group interaction (p < 0.05).

3.3. Cardiovascular dynamics

Group cardiovascular responses are shown in Figure 2. Exercise training or PIO did not significantly affect the rate of change of any cardiovascular variable (Table 3). Within the CON group, HR showed a significantly slower rate of change post‐intervention compared with pre‐intervention (p = 0.01). There was a main effect of time for CO, SV and SVC at both 30 and 240 s (all tests, p < 0.01) mainly due to the higher power outputs achieved post‐training in the exercise groups. However, there was no significant time × group interaction (all tests, p > 0.014). At baseline, post‐training MAP was lower in the CON and higher in the PIO group, while baseline SVC was higher post‐training in the EXC group.

FIGURE 2.

Mean ± SD cardiovascular responses at rest, 30 and 240 s of exercise before (open circles) and after (closed circles) the 12‐week intervention. Statistical outcomes are further described within the results section. CO, cardiac output; HR, heart rate; MAP, mean arterial pressure; SV, stroke volume; SVC, systemic vascular conductance. *Significantly different from pre‐training within the same group (p < 0.05).

4. DISCUSSION

To our knowledge, this is the first study to examine the effects of PIO treatment, with and without exercise training, on cardiorespiratory fitness and oxygen uptake kinetics in individuals with T2D and mild obesity. The main findings were: (1) both PIO‐treated groups (PIO and PIO + EXC), but not exercise alone, showed significant HbA_1c reductions; (2) PIO alone did not significantly improve V̇O_2peak or τV̇O_2p; (3) both exercise groups (EXC and PIO + EXC) significantly improved V̇O_2peak and τV̇O_2p with no difference between them; and (4) the enhanced V̇O₂ kinetics in the exercise groups was not accompanied by changes in cardiovascular dynamics. Together, these findings suggest that while PIO enhances glycaemic control, it does not improve exercise tolerance on its own, and its combination with exercise training does not produce additional synergistic effects on cardiorespiratory adaptations.

4.1. Exercise training‐induced benefits

Both exercising groups showed similar and significant improvements in V̇O_2peak (~9%–12%), indicating the effectiveness of the training intervention. Although no additional verification tests were conducted, the increase in O₂ pulse (improved V̇O_2peak without changes in HR_peak) suggests true physiological adaptations rather than increased effort or test familiarity. This improvement is clinically significant, as higher V̇O_2peak is strongly associated with reduced risk of cardiovascular events and all‐cause mortality. ⁴¹ The magnitude and pattern of V̇O_2peak gains align with previous short‐term aerobic and concurrent training studies in individuals with uncomplicated T2D (see Introduction). These exercise‐induced improvements in V̇O_2peak have been linked to both peripheral and central adaptations. Peripheral adaptations likely include enhanced microvascular oxygen delivery, ²⁹ vascular function improvements, ⁴² vascular structural changes ⁴³ and increased capillary‐to‐myocyte interface ⁴⁴ possibly via increased red blood cell‐flowing capillaries in muscle. ⁴⁵ Central adaptations primarily involve increased left ventricular stroke volume. ⁴⁶

Similarly, both exercise groups showed significant improvements in V̇O₂ kinetics, with a ~17%–20% reduction in τV̇O_2p during moderate‐intensity exercise. These changes align with findings from previous exercise training studies of similar duration in uncomplicated T2D (see introduction). Although not directly demonstrated in T2D, training‐induced changes in τV̇O_2p in clinical conditions such as heart failure or chronic obstructive pulmonary disease are likely driven by the rate at which oxygen is delivered to and/or utilised by the contracting muscles. ¹⁴ , ⁴⁷ In the present study, we evaluated the influence of cardiovascular dynamics (systemic O₂ delivery) by expressing the early changes (30 s) of cardiovascular variables relative to later (240 s) responses. Consistent with recent findings, ⁴⁸ the absence of any training‐related changes herein suggests that submaximal cardiovascular dynamics may remain unaffected by exercise training, but future work using techniques to measure CO with higher temporal resolution is needed. However, this does not preclude a likely upregulated nitric oxide synthase and other mechanisms for increasing more perfusion amidst increasing demands, as exercise training has been shown to enhance the local matching of oxygen delivery to muscle V̇O₂ in T2D. ²⁹ In addition, exercise training increases peak vasodilatory capacity in both, men and women with diabetes, and tends to improve dynamic vasodilatory responses in women with T2D. ⁴⁹

4.2. Effects of PIO

In the present study, PIO therapy, both alone and in combination with exercise, significantly reduced HbA_1c (absolute reductions: ~0.4% and ~0.3%, respectively). This is clinically meaningful, as a 1% absolute HbA_1c reduction is associated with a 15%–20% decrease in major cardiovascular events ⁵⁰ and up to a 37% reduction in microvascular complications. ⁵¹ However, PIO alone did not significantly improve V̇O_2peak (despite increasing it by 4.3%, pairwise post‐hoc p = 0.3) or τV̇O_2p, nor did its combination with exercise produce synergistic effects.

This contrasts with findings by Yokota et al. ³³ who reported significant increases in V̇O_2peak (~8%) after 4 months of PIO treatment (15 mg/day) in males with metabolic syndrome. Earlier studies exploring the impact of rosiglitazone, a different thiazolidinedione, have shown mixed results. For instance, 4 months of rosiglitazone treatment led to improvements in V̇O_2peak (~9%) and some parameters of submaximal V̇O₂, but not in τV̇O_2p, in a more deconditioned cohort (mean baseline V̇O_2peak: 19.8 mL min⁻¹ kg⁻¹) of 5 men and 5 women with uncomplicated T2D. ⁵² On the other hand, combined exercise and rosiglitazone therapy over 8 months produced greater improvements in V̇O_2peak (26.4%) than exercise alone (14.9%) in a larger mixed group of men and women with T2D with more similar baseline fitness levels (V̇O_2peak: ~23 mL min⁻¹ kg⁻¹) to the cohort herein, but poorer baseline glycaemic control (mean HbA_1c: ~8.2%), where rosiglitazone alone also induced significant increases, albeit more modest, in V̇O_2peak (5.4%). ⁵³ In contrast, others reported a decline in aerobic exercise capacity (i.e., shorter duration during incremental exercise) following 12 months of rosiglitazone in individuals with T2D albeit with stable coronary artery disease ⁵⁴ ; and a more recent study found no change in V̇O_2peak after 12 months of rosiglitazone in individuals with prediabetes. ⁵⁵ Collectively, the significant V̇O_2peak improvements with rosiglitazone alone in T2D may be influenced by participants' lower baseline fitness (given the significant correlation between baseline V̇O_2peak and its change following training in T2D), ²⁵ poorer glycaemic control, longer drug exposure and/or different mechanisms of effect of PIO versus rosiglitazone. On the other hand, in contrast with our findings, Kadoglou et al. ⁵³ reported greater improvements in V̇O_2peak with combined rosiglitazone and exercise. This effect was also likely influenced by the participants' suboptimal glycaemic control (all participants began the intervention with HbA_1c > 7%, induced by a 6‐month dose reduction of metformin and gliclazide) as exercise alone reduced HbA_1c (in absolute terms) by 0.51%, rosiglitazone by 0.86%, and the combination by 1.58%, with changes in HbA_1c in the exercising groups correlating with improvements in V̇O_2peak. In our study, however, participants had better baseline glycaemic control, and exercise training did not significantly lower HbA_1c. Consequently, the HbA_1c reduction in the PIO + EXC group was not greater than that seen with PIO alone, and changes in HbA_1c were not correlated with improvements in V̇O_2peak.

In the study by Yokota et al. ³³ the PIO‐induced increases in V̇O_2peak among individuals with metabolic syndrome were accompanied by improvements in skeletal muscle energy metabolism. Although their study lacked a control or placebo group, the authors reported a significant association between the first ventilatory threshold and reductions in intramyocellular lipid content, suggesting enhanced skeletal muscle fatty acid metabolism. This interpretation is further supported by evidence of PIO‐induced upregulation of genes involved in fatty acid oxidation ⁵⁶ and improvements in mitochondrial respiratory capacity ⁵⁷ within skeletal muscle in individuals with T2D. Additionally, PIO has been shown to improve endothelial ⁵⁸ as well as cardiac function, ³⁴ potentially facilitating greater oxygen delivery to working muscles. While these findings suggest that PIO may enhance submaximal exercise capacity and oxygen uptake kinetics through improvements in muscle metabolism and oxygen delivery, such effects were not observed in the present study. One factor that may have contributed to this discrepancy is the commonly reported side effect of PIO‐induced weight gain, typically in the range of 2%–5%, primarily due to fat mass expansion and fluid retention. ⁵⁹ , ⁶⁰ Notably, Bastien et al. found that an increase in subcutaneous fat mass under rosiglitazone therapy strongly predicted a decline in aerobic exercise capacity in T2D. ⁵⁴ In the current study, the PIO group experienced a ~2% gain in body weight, which may have partially offset the potential benefits of PIO on exercise performance, while the combined group only experienced a more modest ~0.9% gain likely mitigated by the exercise intervention.

4.3. Limitations

The main limitations of the present study include the relatively small sample size, the absence of a placebo treatment and the lack of random allocation of participants to experimental groups. Of note, Regensteiner et al. ⁵² detected significant changes in V̇O_2peak and certain parameters of V̇O₂ kinetics following a 4‐month rosiglitazone treatment in a mixed cohort of only 10 participants (5 women) with T2D. However, in a separate study, the same group reported that T2D‐induced reductions in cardiorespiratory fitness were more pronounced in females than males, ⁶¹ raising the possibility that TZDs might influence exercise performance in T2D in a sex‐specific manner. In contrast, our cohort was more homogeneous, comprising only men with similar baseline activity levels, aerobic capacity and metabolic status across groups. In addition, while the current study initially aimed to include both sexes, slower female enrolment and time constraints led to the recruitment of men only. Of note, two women in the PIO + EX group completed the intervention, and combining all participants' data (i.e., PIO + EX, n = 9) did not alter study outcomes (data not shown). The current findings are applicable to male individuals with uncomplicated T2D. Future randomized controlled trials are necessary to more conclusively determine the effects of PIO on exercise tolerance in men and women with type 2 diabetes. Such trials should assess changes in body composition to better interpret weight changes, and include a follow‐up phase after the intervention to confirm its effectiveness.

5. CONCLUSION

In conclusion, although PIO significantly improved glycaemic control over the 12‐week intervention, it did not replicate the improvements in peak aerobic capacity or V̇O₂ kinetics achieved through exercise training. Furthermore, combining PIO with exercise did not produce any additional benefits in exercise tolerance beyond those conferred by exercise alone. These findings suggest that to improve exercise performance, males with uncomplicated T2D receiving PIO should engage in regular exercise.

AUTHOR CONTRIBUTIONS

EO'C, CK, DO'S, SG and ME designed the study; EO'C and CK collected data; ME drafted the manuscript; EO'C, CK, NG, DO'S, SG and ME analysed the results and approved the final version of the manuscript.

CONFLICT OF INTEREST STATEMENT

The authors declare no conflicts of interest.

PEER REVIEW

The peer review history for this article is available at https://www.webofscience.com/api/gateway/wos/peer‐review/10.1111/dom.16648.

Supporting information

Figure S1. Participant flow chart diagram.

Figure S2. Oxygen uptake (V̇O₂) responses for representative individuals in each group during moderate‐intensity cycling transitions pre‐ (open circles) and post‐ (solid circles) intervention. The continuous lines of best fit illustrate the primary phase of the oxygen uptake response (τV̇O_2p). Note the relatively slower response of the τV̇O_2p response in the pre‐ compared with the post‐intervention in the exercise and pioglitazone + exercise groups.

Table S1. Summary of the key measurement variables obtained during the intervention.

O'Connor E, Kiely C, Gildea N, O'Shea D, Green S, Egaña M. Effects of pioglitazone with and without exercise training on cardiorespiratory fitness and oxygen uptake kinetics in type 2 diabetes. Diabetes Obes Metab. 2025;27(10):5910‐5920. doi: 10.1111/dom.16648

DATA AVAILABILITY STATEMENT

Data will be made available on request from the corresponding author.