👤 Martijn J L Bours

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

Obesity is a major global health issue with multifactorial etiologies. Among them, recent advances in the comprehension of eating and energy regulation showed that around 60 genes involved in the hypothalamic leptin/melanocortin pathway contribute to the development of rare monogenic or syndromic forms of obesity. To better delineate the genetic diagnostic rate and the phenotype in a cohort of early onset obesity and to integrate our results in guidance for genetic testing. In a diagnostic setting, 223 patients with early onset obesity were screened through a targeted panel including 44 genes for severe early onset obesity. Genetic results and clinical descriptions were reviewed for the entire cohort. A diagnostic yield of 3.1% was established. Likely pathogenic or pathogenic variants were found in Our work found a diagnostic yield of 3.1%. Additionally, 19.7% of heterozygous variants of unknown significance were found in genes related to autosomal conditions and 34.9% in genes related to recessive conditions. These results highlight the need for accurate genotype-phenotype correlations. Genetic laboratory expertise in obesity is highly recommended, especially in the context of the availability of new targeted anti-obesity therapies that open the field for current and future perspectives of these targeted genetic investigations. Show less

Disrupted diurnal rest-activity rhythms (RAR), that is, daily 24-h patterns of rest and activity, have been associated with fatigue and decreased quality of life among survivors of colorectal cancer (CRC). To identify potential targets for interventions to improve RAR, we investigated longitudinal associations of time spent in sedentary behavior and physical activity with RAR parameters after CRC treatment. In a prospective cohort study, repeated measurements were performed among 268 survivors of stage I-III CRC at 6 weeks, 6 months, and 1, 2, and 5 years after treatment. Thigh-worn accelerometers were used to determine hours/day spent in sedentary behavior, standing, and total physical activity during waking time, as well as RAR parameters including mesor, amplitude, circadian quotient (CQ), dichotomy index (I < O) and 24 h-autocorrelation (R24). Self-reported light-intensity physical activity (LPA) and moderate-to-vigorous physical activity (MVPA) were determined via the validated SQUASH questionnaire. Longitudinal associations were analyzed using confounder-adjusted linear mixed models. More sedentary time was statistically significantly associated with a lower mesor, amplitude, I < O and R24 over the 5-year post-treatment period. More standing time was associated with a higher mesor, amplitude, CQ, and I < O but not with R24. Higher levels of objectively assessed total physical activity as well as self-reported MVPA were associated with higher values for all RAR parameters. LPA was not associated with any of the RAR parameters. In the years after CRC treatment, less sedentary behavior and more standing and physical activity were generally associated with higher RAR parameters indicating a more robust rhythm. Future studies should provide more insight into causality of these associations as RAR may be a potential new target for interventions to reduce fatigue after CRC.Trial registration: EnCoRe study NL6904 (https://www.Onderzoekmetmensen.nl/). Show less

Branched-chain amino acids (BCAA) are essential amino acids playing crucial roles in protein synthesis and brain neurotransmission. Branched-chain ketoacid dehydrogenase (BCKDH), the flux-generating step of BCAA catabolism, is tightly regulated by reversible phosphorylation of its E1α-subunit. BCKDK is the kinase responsible for the phosphorylation-mediated inactivation of BCKDH. In three siblings with severe developmental delays, microcephaly, autism spectrum disorder and epileptic encephalopathy, we identified a new homozygous in-frame deletion (c.999₁₀₀₁delCAC; p.Thr334del) of Show less

The neuroendocrine control of reproduction in mammals is governed by a neural hypothalamic network of nearly 1500 gonadotropin-releasing hormone (GnRH) secreting neurons that modulate the activity of the reproductive axis across life. Congenital hypogonadotropic hypogonadism (HH) is a clinical syndrome that is characterized by partial or complete pubertal failure. HH may result from inadequate hypothalamic GnRH axis activation, or a failure of pituitary gonadotropin secretion/effects. In man, several genes that participate in olfactory and GnRH neuronal migration are thought to interact during the embryonic life. A growing number of mutations in different genes are responsible for congenital HH. Based on the presence or absence of olfaction dysfunction, HH is divided in two syndromes: HH with olfactory alterations [Kallmann syndrome (KS)] and idiopathic hypogonadotropic hypogonadism (IHH) with normal smell (normosmic IHH). KS is a heterogeneous disorder affecting 1 in 5000 males, with a three to fivefold of males over females. KS is associated with mutations in KAL1, FGFR1/FGF8, FGF17, IL17RD, PROK2/PROKR2, NELF, CHD7, HS6ST1, FLRT3, SPRY4, DUSP6, SEMA3A, NELF, and WDR11 genes that are related to defects in neuronal migration. These reproductive and olfactory deficits include a variable non-reproductive phenotype, including sensorineural deafness, coloboma, bimanual synkinesis, craniofacial abnormalities, and/or renal agenesis. Interestingly, defects in PROKR2, FGFR1, FGF8, CHD7, DUSP6, and WDR11 genes are also associated with normosmic IHH, whereas mutations in KISS1/KISSR, TAC3/TACR3, GNRH1/GNRHR, LEP/LEPR, HESX1, FSHB, and LHB are only present in patients with normosmic IHH. In this paper, we summarize the reproductive, neurodevelopmental, and genetic aspects of HH in human pathology. Show less