IntroductionDiabetic foot ulcer represents a major health problem globally. Preliminary studies have indicated that systemic treatment of diabetic foot ulcer patients with hyperbaric oxygen therapy have beneficial effects on wound healing, risk of amputation, glycaemic control, atherosclerosis, inflammatory markers and other clinical and laboratory parameters. This protocol for a systematic review aims at identifying the beneficial and harmful effects of adding hyperbaric oxygen therapy to standard wound care for diabetic foot ulcers.Methods and analysisThis protocol was performed following the recommendations of the Cochrane Collaboration and the eight-step assessment procedure suggested by Jakobsen and colleagues. We plan to include all relevant randomised clinical trials assessing the effects of hyperbaric oxygen therapy in the treatment of diabetic foot ulcer versus any control group with any intervention defined as standard wound care or similar, together with sham interventions. Our primary outcome will be: all-cause mortality, serious adverse events and quality of life. Our secondary outcomes will be: healing of index wound, major amputation and wound infection. Any eligible trial will be assessed and classified as either high risk of bias or low risk of bias, and our conclusions will be based on trials with low risk of bias. The analyses of the extracted data will be performed using Review Manager 5 and Trial Sequential Analysis. For both our primary and secondary outcomes, we will create a ‘Summary of Findings’ table and use GRADE (Grading of Recommendations Assessment, Development and Evaluation) assessment to assess the quality of the evidence.Ethics and disseminationWe use publicly accessible documents as evidence, there is no participant involvement at an individual level and an institutional ethics approval is not required. The results of the review will be sought published in a peer-reviewed journals, also in the event of insignificant results or null results, and thereby it will be disseminated to clinicians and public available.PROSPERO registration numberCRD42019139256.

IntroductionIn general, patients with type 2 diabetes have lower cardiorespiratory fitness levels and perform exercise at lower intensities compared to healthy controls. Since metformin (MET) has been shown to increase the rate of perceived exertion (RPE) during exercise with a fixed intensity, MET per se may reduce self-selected exercise intensity. The aim of this study was to assess the effect of MET on self-selected exercise intensity.MethodsHealthy males were eligible for this crossover, counterbalanced study with two treatment periods: MET and placebo (PLA), each lasting 17 days. Treatment dose was gradually increased and reached 2 g/day on treatment day 9, and continued at that level for the rest of the treatment period. The two periods were performed in randomized order. Two experimental days (A+B) were conducted on Day 15 (A) and Day 17 (B) of each period, respectively. Day A consisted of an exercise bout with self-selected exercise intensity (equal to RPE = 14–15 on the Borg Scale). Day B consisted of an exercise bout with fixed intensity (70% of VO2peak). Oxygen consumption rate was assessed continuously during both exercise bouts.ResultsFifteen males (age 23.7 ± 0.6 years, BMI 22.3 ± 2.0, VO2peak 3.5 ± 0.6 L/min) were included in the study. On Day B, RPE was higher in MET compared to PLA (14.8 ± 0.4 vs. 14.0 ± 0.3, P = 0.045). On Day A, no difference in self-selected exercise intensity measured by oxygen consumption rate (PLA 2.33 ± 0.09 L O2/min, MET 2.42 ± 0.10 L O2/min, P = 0.09) was seen between treatment periods.ConclusionsSelf-selected exercise intensity was not reduced by MET in healthy males, despite the fact that MET increased RPE during an exercise bout with fixed intensity.

Metformin and exercise both improve glycemic control, but in vitro studies have indicated that an interaction between metformin and exercise occurs in skeletal muscle, suggesting a blunting effect of metformin on exercise training adaptations. Two studies (a double-blind, parallel-group, randomized clinical trial conducted in 29 glucose-intolerant individuals and a double-blind, cross-over trial conducted in 15 healthy lean males) were included in this paper. In both studies, the effect of acute exercise +/- metformin treatment on different skeletal muscle variables, previously suggested to be involved in a pharmaco-physiological interaction between metformin and exercise, was assessed. Furthermore, in the parallel-group trial, the effect of 12 weeks of exercise training was assessed. Skeletal muscle biopsies were obtained before and after acute exercise and 12 weeks of exercise training, and mitochondrial respiration, oxidative stress and AMPK activation was determined. Metformin did not significantly affect the effects of acute exercise or exercise training on mitochondrial respiration, oxidative stress or AMPK activation, indicating that the response to acute exercise and exercise training adaptations in skeletal muscle is not affected by metformin treatment. Further studies are needed to investigate whether an interaction between metformin and exercise is present in other tissues, e.g. the gut. Trial registration: ClinicalTrials.gov (NCT03316690 and NCT02951260). Novelty bullets • Metformin does not affect exercise-induced alterations in mitochondrial respiratory capacity in human skeletal muscle • Metformin does not affect exercise-induced alterations in systemic levels of oxidative stress nor emission of reactive oxygen species from human skeletal muscle • Metformin does not affect exercise-induced AMPK activation in human skeletal muscle