👤 Hella van der Velde

The timing of physical activity may influence metabolic health through interactions with circadian rhythms, yet its role in type 2 diabetes mellitus (T2DM) development is unclear. We investigated associations between time-of-day-specific physical activity and incident T2DM, and whether theoretically reallocating activity from morning to later in the day was associated with changes in T2DM risk. We included 4615 participants from The Maastricht Study cohort without diabetes (age 59.2 ± 8.6 years; 56.3% women). Device-based physical activity was measured over 7 days using activPAL monitors and classified into light-intensity physical activity (LPA) and moderate-to-vigorous intensity physical activity (MVPA), for morning (06:00-11:59 AM), afternoon (12:00-17:59 PM), evening (18:00-23:59 PM) and night (00:00-05:59 AM). Incident T2DM was assessed during a median 8.2-year follow-up. Cox proportional hazard and isotemporal substitution models were used, adjusted for sociodemographic and lifestyle factors, including diet, employment and sleep duration. During follow-up, 168 participants (3.6%) developed T2DM. Each additional 10 min/day of afternoon LPA or MVPA was associated with lower T2DM risk (LPA: hazard ratio [HR] 0.82, 95% confidence interval [CI] 0.70-0.97; MVPA: HR 0.85, 95% CI 0.72-1.00). Evening MVPA was also inversely associated with T2DM risk (0.65; 0.45-0.93), whereas night-time MVPA was associated with an increased risk (3.64; 1.30-10.17). No significant associations were found of morning LPA and MVPA or evening and night LPA with T2DM incidence. Substitution analyses indicated that reallocating 10 min of morning LPA to afternoon LPA (HR 0.71; 0.54-0.95) or morning MVPA to evening MVPA (HR: 0.64; 0.43-0.96) was associated with a lower T2DM risk, while no other significant associations were observed. Later-day physical activity, particularly in the afternoon, was associated with a lower incidence of T2DM, independent of intensity. This highlights the potential relevance of activity timing in relation to T2DM incidence. Show less

The standard model of Wnt signaling specifies that after receipt of a Wnt ligand at the membranous receptor complex, downstream mediators inhibit a cytoplasmic destruction complex, allowing beta-catenin to accumulate in the cytosol and nucleus and co-activate Wnt target genes. Unexpectedly, shortly after Wnt treatment, we detected the dephosphorylated form of beta-catenin at the plasma membrane, where it displayed a discontinuous punctate labeling. This pool of beta-catenin could only be detected in E-cadherin(-/-) cells, because in E-cadherin(+/+) cells Wnt-induced, membranous beta-catenin was concealed by a constitutive junctional pool. Wnt-signaling-dependent dephosphorylated beta-catenin colocalized at the plasma membrane with two members of the destruction complex -- APC and axin -- and the activated Wnt co-receptor LRP6. beta-catenin induced through the Wnt receptor complex was significantly more competent transcriptionally than overexpressed beta-catenin, both in cultured cells and in early Xenopus embryos. Our data reveal a new step in the processing of the Wnt signal and suggest regulation of signaling output beyond the level of protein accumulation. Show less