Effects of Metformin and Exercise Training, Alone or in Combination, on Cardiac Function in Individuals with Insulin Resistance

Male and female subjects were consecutively recruited from individuals screened at the Diabetic Center at our University Hospital (University of Cagliari). No sponsorship was received to perform the study. The study was spontaneous and blinded to the investigators. All of the patients presented with recently identified impaired glucose tolerance (IGT), defined as 2 h values in the oral glucose tolerance test (OGTT) of 140–199 mg/dL and/or impaired fasting glucose (IFG), defined as fasting glucose levels of 100–125 mg/dL. OGTT was performed to assess glucose and insulin in the fasting state and every 30 min up to 2 h after ingesting a glucose load (75 g). All of the subjects enrolled were affected by IR, defined according to the values of the homeostatic model assessment (HOMA) index (>2.77) described by Bonora et al. [15].

The inclusion criteria for all IR patients were as follows: age 20–55 years, echocardiographic LV ejection fraction (LVEF) ≥55%; absence of LV wall motion abnormalities; and normal renal and hepatic function (bilirubin ≤1.5 mg/dL, creatinine ≤2.0 mg/dL). The exclusion criteria were: current smoker; presence of diabetes; hypertension with LV hypertrophy; obesity (overweight patients were accepted with body mass index <29.9 kg/m²); atrial fibrillation or severe arrhythmias; and moderate-to-severe heart valve disease. Patients with hypertension without LV hypertrophy or dyslipidemia were included in the study.

At enrollment, all of the subjects underwent a physical examination, 12-lead electrocardiogram, standard cardiopulmonary (CP) exercise test (CPET), complete blood chemistry, standard echocardiography (M-mode, 2D and Doppler), tissue Doppler imaging (TDI) and evaluation of global longitudinal strain (GLS) and global longitudinal strain rate (GLSR) parameters with STE. All of the patients were subsequently allocated to the three treatment groups (1:1:1) and re-evaluated after 12 weeks: Group M received 12 weeks of MET treatment; Group Ex received 12 weeks of supervised exercise therapy; and Group MEx received 12 weeks of MET therapy plus supervised exercise. Patients receiving therapy with MET started treatment at a dose of 500 mg/day. The dose was increased to the clinical dose of 1000 mg/day in the second week. This dose was administered for the remaining 11 weeks of the study.

Using a commercially available system (Toshiba Artida™; Toshiba Corp., Tochigi, Japan), echocardiographic images were recorded. LVEF was obtained according to biplane Simpson’s rule and considered abnormal at <55%. From the four-chamber view, a pulsed wave Doppler (PWD) examination of the LV inflow was performed. The sample volume was placed between the mitral leaflet tips to evaluate the early (E) and late (A) diastolic peak velocities. The E/A ratio was derived and deceleration time (DecT) of the E wave was measured.

A four- and two-chamber view clip was acquired at each evaluation. The longitudinal ventricular function at baseline and after exercise was calculated offline using raw data (Toshiba Corp., Tochigi, Japan). GLS and GLSR were obtained by averaging the strain and strain rate of all LV segments in the four-chamber and two-chamber view.

To achieve homogeneous acquisition of data and images, all of the echocardiographic examinations were performed by the same operator (C.C.). All of the offline measurements were performed by a single investigator (M.D.) who was blinded to the clinical condition of the study participants. The intra-observer variability in our laboratory has been documented previously [16].

The same exercise training protocol was performed in both the exercise groups (Ex and MEx). The training program encompassed stretching exercises, and warm-up, central and cool down phases. The central phase included cycle ergometer training at the anaerobic threshold level, which was performed for 60 min/day four times per week for 12 weeks at our laboratory. After 6 weeks, each subject underwent a CPET to readjust the training workload [17].

All procedures followed were in accordance with the ethical standards of the responsible committee on human experimentation (ethics committees of the University of Cagliari, Italy) and with the Helsinki Declaration of 1964, as revised in 2013. Informed consent was obtained from all patients prior to inclusion in the study.

In humans, most reports in the literature investigating IR and cardiac dysfunction refer to the deterioration of diastolic function [20, 21]. However, IR can lead to impaired myocardial systolic function, potentially through altered calcium homeostasis, increased oxidative stress, altered substrate metabolism, and mitochondrial dysfunction [22]. Thus, there is a link between pre-diabetes and heart failure. A vast majority of individuals with heart failure have stable IR, which, in turn, correlates with the severity of the disease and outcomes [23, 24]. Some years ago Ingelsson et al. showed in a large population that IR is correlated with the incidence of heart failure independently of known risk factors, including diabetes [25].

In the setting of heart failure, the reduced cardiac output and increased adrenergic activation, both of which are responsible for sub-optimal tissue perfusion, could lead to IR and impaired glucose tolerance. Nevertheless, insulin-resistant overt cardiomyopathy has been described in relation to an inefficiency in myocardial energy [26].

IR determines energy inadequacy in cardiomyocytes due to an increased recourse to fatty acids, which are energetically less efficient than glucose. Furthermore, in contrast to those in healthy subjects, the cardiomyocytes of patients with IR are not able to use glucose under conditions of stress. These mechanisms, which are associated with endothelial impairment in IR patients, may contribute to the reduction of both cardiopulmonary performance [9] and myocardial contractile reserves [13, 14].

One treatment option for pre-diabetic patients is the biguanide MET. In diabetic patients, MET has been associated with improved outcomes [27]. In the US DPP, MET was demonstrated to reduce the evolution from a condition of glucose intolerance to diabetes [28, 29]. A beneficial effect on systolic function after 3 months of MET therapy has been previously described in animal models of heart failure, in which it was demonstrated that administration of the drug provides significant cardio-protective effects and improves LV function [30, 31]. In patients with heart failure, the use of MET was shown to cause an increase in systolic function with better outcomes compared to other treatments [32, 33]. Wong et al. recently demonstrated a positive effect of MET treatment on LV function in IR patients with advanced heart failure [34]. They showed that LVEF recovers only when the treatment with MET is accompanied by a decrease in brain natriuretic peptide, thereby suggesting that MET may improve systolic function by decreasing cardiac overload. The present study, using the reliable STE technique, confirmed the ability of MET to significantly improve LV systolic function in an IR population.

The detailed mechanisms by which MET exerts its beneficial effects appear to be related to a decrease in free fatty acid levels, reduction of myocardial lipid accumulation, diminished perivascular fibrosis, and AMPK-eNOS signal activation [30]. However, MET has several limitations concerning its use, and various adverse events have been reported. MET may cause a decrease in VO2 in subjects with no IR [8], and our previous data have demonstrated the same effect in patients with IR [9]. It is of importance that this effect does not occur in every patient but mainly in those with a lower degree of IR; in contrast, CP performance is significantly increased in subjects with a high degree of IR. In patients with heart failure, MET significantly improves IR and the pulmonary ventilation/ventilator carbon dioxide slope, leading to significant weight loss; however, it is unable to increase the peak VO2 [34].

Regular exercise increases the peripheral sensitivity to insulin mainly of skeletal muscle, largely by stimulating AMPK [35, 36]. The American Diabetes Association strongly recommends exercise as a cornerstone therapy for the prevention of diabetes, and the combination of exercise and MET has been proposed in place of each of the two separate therapies [17]. Currently available data suggest an advantage of the addition of metformin to physical training in terms of weight loss [37] but negligible or no effect on IR [38]. Insulin sensitivity in pre-diabetic subjects can be increased by physical exercise, but the association with MET does not determine a further advantage in terms of sensitivity to the hormone and can even attenuate the effect of the physical training [10].

In a previous study, we showed that the association with physical training could compensate the negative effects of MET on cardiopulmonary performance. Furthermore, we demonstrated that physical exercise, when personalized and supervised, affected cardiopulmonary parameters and quality of life similar to the combination of MET and exercise [11]. Moreover, there are limited data for the effect of physical training alone or in combination with MET on LV cardiac function. Stewart et al. showed that 6 months of exercise had no effect on cardiac dimensions or on LV diastolic function despite a significant increase in cardiopulmonary performance in terms of peak VO2 [39].

To our knowledge, the present results show for the first time that physical training alone does affect LV cardiac function despite the improvements in cardiopulmonary performance. However, the association between supervised exercise and MET does not reduce the positive effects of the drug on the indices of LV systolic function and retains its positive influence on exercise capacity in terms of peak VO2. At present, however, it remains unknown whether the beneficial effects on the indices of myocardial performance at rest can be preserved during physical activity in terms of contractile reserve and cardiac performance.

In agreement with the results of previous studies, we did not observe any improvement in the indices of diastolic function after physical training [39], or even after MET alone or in combination with exercise. Moreover, a beneficial effect of MET on diastolic function was recently hypothesized and proposed as a rational endpoint in a randomized trial [40].

The main limitation of the study is related to the study design. A single-blinded design was chosen due to the difficulties of concealing the exercise aspect of treatment. Moreover, patients were not randomized to a treatment group and rather were allocated a treatment based on consecutive enrollment to the study.