The blockade of glucocorticoid (GC) action through antagonism of the glucocorticoid receptor II (GRII) has been used to minimize the undesirable effects of chronically elevated GC levels. Mifepristone (RU486) is known to competitively block GRII action, but not exclusively, as it antagonizes the progesterone receptor. A number of new selective GRII antagonists have been developed, but limited testing has been completed in animal models of overt type 2 diabetes mellitus. Therefore, two selective GRII antagonists (C113176 and C108297) were tested to determine their effects in our model of GC-induced rapid-onset diabetes (ROD). Male Sprague-Dawley rats (∼ six weeks of age) were placed on a high-fat diet (60%), surgically implanted with pellets containing corticosterone (CORT) or wax (control) and divided into five treatment groups. Each group was treated with either a GRII antagonist or vehicle for 14 days after surgery: CORT pellets (400 mg/rat) + antagonists (80 mg/kg/day); CORT pellets + drug vehicle; and wax pellets (control) + drug vehicle. After 10 days of CORT treatment, body mass gain was increased with RU486 (by ∼20% from baseline) and maintained with C113176 administration, whereas rats given C108297 had similar body mass loss (∼15%) to ROD animals. Fasting glycemia was elevated in the ROD animals (>20 mM), normalized completely in animals treated with RU486 (6.2±0.1 mM, p<0.05) and improved in animals treated with C108297 and C113176 (14.0±1.6 and 8.8±1.6 mM, p<0.05 respectively). Glucose intolerance was normalized with RU486 treatment, whereas acute insulin response was improved with RU486 and C113176 treatment. Also, peripheral insulin resistance was attenuated with C113176 treatment along with improved levels of β-cell function while C108297 antagonism only provided modest improvements. In summary, C113176 is an effective agent that minimized some GC-induced detrimental metabolic effects and may provide an alternative to the effective, but non-selective, GRII antagonist RU486.

Background: Fluctuations in endogenous hormones estrogen and progesterone during the menstrual cycle may offer vasoprotection for endothelial and smooth muscle (VSM) function. While numerous studies have been published, the results are conflicting, leaving our understanding of the impact of the menstrual cycle on vascular function unclear. The purpose of this systematic review and meta-analysis was to consolidate available research exploring the role of the menstrual cycle on peripheral vascular function. Methods: A systematic search of MEDLINE, Web of Science, and EMBASE was performed for articles evaluating peripheral endothelial and VSM function across the natural menstrual cycle: early follicular (EF) phase versus late follicular (LF), early luteal, mid luteal, or late luteal. A meta-analysis examined the effect of the menstrual cycle on the standardized mean difference (SMD) of the outcome measures. Results: Analysis from 30 studies (n=1,363 women) observed a "very low" certainty of evidence that endothelial function increased in the LF phase (SMD:0.45,p=0.0001), with differences observed in the macrovasculature but not the microvasculature (SMD:0.57,p=0.0003, I2=84%; SMD:0.21,p=0.17,I2=34% respectively). However, these results are partially explained by differences in FMD [ex. discrete (SMD: 0.86, p=0.001) versus continuous peak diameter assessment (SMD: 0.25, p = 0.30)] and/or menstrual cycle phase methodologies. There was a "very low" certainty that endothelial function was largely unchanged in the luteal phases, and VSM was unchanged across the cycle. Conclusions: The menstrual cycle appears to have a small effect on macrovascular endothelial function, but not microvascular or VSM function; however, these results can be partially attributed to methodological differences.

Background: Cardiac rehabilitation exercise reduces the risk of secondary cardiovascular disease. Interval training is a time-efficient alternative to traditional cardiac rehabilitation exercise and stair climbing is an accessible means. We aimed to assess the effectiveness of a high-intensity interval stair climbing intervention on improving cardiorespiratory fitness (V˙O2peak) compared to standard cardiac rehabilitation care.Methods: Twenty participants with coronary artery disease (61 ± 7 years, 18 males, two females) were randomly assigned to either traditional moderate-intensity exercise (TRAD) or high-intensity interval stair climbing (STAIR). V˙O2peak was assessed at baseline, following 4 weeks of six supervised exercise sessions and after 8 weeks of ~24 unsupervised exercise sessions. TRAD involved a minimum of 30 min at 60–80%HRpeak, and STAIR consisted of three bouts of six flights of 12 stairs at a self-selected vigorous intensity (~90 s/bout) separated by recovery periods of walking (~90 s). This study was registered as a clinical trial at clinicaltrials.gov (NCT03235674).Results: Two participants could not complete the trial due to the time commitment of the testing visits, leaving n = 9 in each group who completed the interventions without any adverse events. V˙O2peak increased after supervised and unsupervised training in comparison to baseline for both TRAD [baseline: 22.9 ± 2.5, 4 weeks (supervised): 25.3 ± 4.4, and 12 weeks (unsupervised): 26.5 ± 4.8 mL/kg/min] and STAIR [baseline: 21.4 ± 4.5, 4 weeks (supervised): 23.4 ± 5.6, and 12 weeks (unsupervised): 25 ± 6.2 mL/kg/min; p (time) = 0.03]. During the first 4 weeks of training (supervised) the STAIR vs. TRAD group had a higher %HRpeak (101 ± 1 vs. 89 ± 1%; p ≤ 0.001), across a shorter total exercise time (7.1 ± 0.1 vs. 36.7 ± 1.1 min; p = 0.009). During the subsequent 8 weeks of unsupervised training, %HRpeak was not different (87 ± 8 vs. 96 ± 8%; p = 0.055, mean ± SD) between groups, however, the STAIR group continued to exercise for less time per session (10.0 ± 3.2 vs. 24.2 ± 17.0 min; p = 0.036).Conclusions: Both brief, vigorous stair climbing, and traditional moderate-intensity exercise are effective in increasing V˙O2peak, in cardiac rehabilitation exercise programmes.

Diabetes is rapidly induced in young male Sprague-Dawley rats following treatment with exogenous corticosterone (CORT) and a high-fat diet (HFD). Regular exercise alleviates insulin insensitivity and improves pancreatic β-cell function in insulin-resistant/diabetic rodents, but its effect in an animal model of elevated glucocorticoids is unknown. We examined the effect of voluntary exercise (EX) on diabetes development in CORT-HFD-treated male Sprague-Dawley rats (∼6 wk old). Animals were acclimatized to running wheels for 2 wk, then given a HFD, either wax (placebo) or CORT pellets, and split into 4 groups: placebo-sedentary (SED) or -EX and CORT-SED or -EX. After 2 wk of running combined with treatment, CORT-EX animals had reduced visceral adiposity, and increased skeletal muscle type IIb/x fiber area, oxidative capacity, capillary-to-fiber ratio and insulin sensitivity compared with CORT-SED animals (all P < 0.05). Although CORT-EX animals still had fasting hyperglycemia, these values were significantly improved compared with CORT-SED animals (14.3 ± 1.6 vs. 18.8 ± 0.9 mM). In addition, acute in vivo insulin response to an oral glucose challenge was enhanced ∼2-fold in CORT-EX vs. CORT-SED (P < 0.05) which was further demonstrated ex vivo in isolated islets. We conclude that voluntary wheel running in rats improves, but does not fully normalize, the metabolic profile and skeletal muscle composition of animals administered CORT and HFD.

Glucocorticoids (GCs) are steroid hormones, naturally produced by activation of the hypothalamic-pituitary-adrenal (HPA) axis, that mediate the immune and metabolic systems. Synthetic GCs are used to treat a number of inflammatory conditions and diseases including lupus and rheumatoid arthritis. Generally, chronic or high dose GC administration is associated with side effects such as steroid-induced skeletal muscle loss, visceral adiposity, and diabetes development. Patients who are taking exogenous GCs could also be more susceptible to poor food choices, but the effect that increasing fat consumption in combination with elevated exogenous GCs has only recently been investigated. Overall, these studies show that the damaging metabolic effects initiated through exogenous GC treatment are significantly amplified when combined with a high fat diet (HFD). Rodent studies of a HFD and elevated GCs demonstrate more glucose intolerance, hyperinsulinemia, visceral adiposity, and skeletal muscle lipid deposition when compared to rodents subjected to either treatment on its own. Exercise has recently been shown to be a viable therapeutic option for GC-treated, high-fat fed rodents, with the potential mechanisms still being examined. Clinically, these mechanistic studies underscore the importance of a low fat diet and increased physical activity levels when individuals are given a course of GC treatment.