Hypertrophy and dysfunction of the urinary bladder are consistently observed in animal models of type 1 and less consistently in those of type 2 diabetes. We have tested the effects of mild hyperglycemia (n = 10 per group) in a randomized, blinded study and, in a blinded pilot study, of type 2 diabetes (n = 6 per group) and its treatment with dapagliflozin (1 mg/kg/day) on weight, contraction and relaxation of the rat bladder. Based on a combination of high-fat diet and a low dose of streptozotocin, animals in the main study reached a mean peak blood glucose level of about 300 mg/dl, which declined to 205 mg/dl at study end. This was associated with a small if any increase in bladder weight. In a pooled analysis of all animals of the main and the pilot study, we detected a correlation of moderate strength between blood glucose and bladder weight (r2 = 0.2013; P = 0.0003 for Pearson correlation coefficient). Neither the main nor the pilot study found evidence for an altered contractility (responses to carbachol or KCl) or relaxation (responses to isoprenaline, fenoterol, CL 316,243 or forskolin). Treatment with dapagliflozin in the absence of hyperglycemia increased diuresis in the main study by 43% relative to control and increased bladder weight by 15% in the pooled groups of both studies (post-hoc analysis). We conclude that mild hyperglycemia has no major effects on bladder hypertrophy or function.

Using two examples from the non-scientific literature, we show how choice of unit of measure and scaling of y-axis can caused a biased perception of data, a phenomenon we propose to call perception bias. We recommend to pre-specify unit of measure or how it will be determined, whether outcome variables will be shown as absolute or relative/normalized changes, and to typically start y-axis at 0 for ratio variables.

Diabetes is a chronic, endocrine disorder that effects millions of people worldwide. Cardiovascular complications are the major cause of diabetes-related morbidity and mortality. Cardiac β₁- and β₂-adrenoceptor (AR) stimulation mediates positive inotropy and chronotropy, whereas β₃-AR mediates negative inotropic effect. Changes in β-AR responsiveness are thought to be an important factor that contributes to the diabetic cardiac dysfunction. Diabetes related changes in β-AR expression, signaling, and β-AR mediated cardiac function have been studied by several investigators for many years. In the present review, we have screened PubMed database to obtain relevant articles on this topic. Our search has ended up with wide range of different findings about the effect of diabetes on β-AR mediated changes both in molecular and functional level. Considering these inconsistent findings, the effect of diabetes on cardiac β-AR still remains to be clarified.

Nonclinical studies form the basis for the decision whether to take a therapeutic candidate into the clinic. These studies need to exhibit translational robustness for both ethical and economic reasons. Key findings confirmed in multiple species have a greater chance to also occur in humans. Given the heterogeneity of patient populations, preclinical studies or at least programs comprising multiple studies need to reflect such heterogeneity, e.g., regarding strains, sex, age, and comorbidities of experimental animals. However, introducing such heterogeneity requires larger studies/programs to maintain statistical power in the face of greater variability. In addition to classic sources of bias, e.g., related to lack of randomization and concealment, translational studies face specific sources of potential bias such as that introduced by a model that may not reflect the full spectrum of underlying pathophysiology in patients, that defined by timing of treatment, or that implied in dosing decisions and interspecies differences in pharmacokinetic profiles. The balance of all these factors needs to be considered carefully for each study and program.

Numerous studies in airways, ileum, and urinary bladder have demonstrated that relaxation by β-adrenoceptor agonists has lower potency and/or efficacy when contraction was elicited by muscarinic receptor agonists as compared to other G-protein-coupled receptors, KCl, or basal tone, but the molecular mechanisms behind this relative resistance remain unclear. A paper by Huang et al. in this issue demonstrates that NAV2729, an inhibitor of ADP ribosylation factor 6, inhibits contraction of isolated blood vessels elicited by muscarinic receptor agonists, but not by α₁-adrenoceptor agonists or KCl. Against this background, we discuss the role of ADP ribosylation factor 6 in cellular responses to G-protein-coupled receptor stimulation. While ADP ribosylation factor 6 apparently is the only promising molecular explanation for the relative resistance of smooth muscle contraction elicited by muscarinic agonists, the existing data are insufficient for a robust conclusion.