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Aims/hypothesis: The circadian system plays an essential role in regulating the timing of human metabolism. Indeed, circadian misalignment is strongly associated with high rates of metabolic disorders. The properties of the circadian oscillator can be measured in cells cultured in vitro and these cellular rhythms are highly informative of the physiological circadian rhythm in vivo. We aimed to discover whether molecular properties of the circadian oscillator are altered as a result of type 2 diabetes. Methods: We assessed molecular clock properties in dermal fibroblasts established from skin biopsies taken from nine obese and eight non-obese individuals with type 2 diabetes and 11 non-diabetic control individuals. Following in vitro synchronisation, primary fibroblast cultures were subjected to continuous assessment of circadian bioluminescence profiles based on lentiviral luciferase reporters. Results: We observed a significant inverse correlation (ρ = −0.592; p < 0.05) between HbA1c values and circadian period length within cells from the type 2 diabetes group. RNA sequencing analysis conducted on samples from this group revealed that ICAM1, encoding the endothelial adhesion protein, was differentially expressed in fibroblasts from individuals with poorly controlled vs well-controlled type 2 diabetes and its levels correlated with cellular period length. Consistent with this circadian link, the ICAM1 gene also displayed rhythmic binding of the circadian locomotor output cycles kaput (CLOCK) protein that correlated with gene expression. Conclusions/interpretation: We provide for the first time a potential molecular link between glycaemic control in individuals with type 2 diabetes and circadian clock machinery. This paves the way for further mechanistic understanding of circadian oscillator changes upon type 2 diabetes development in humans. Data availability: RNA sequencing data and clinical phenotypic data have been deposited at the European Genome-phenome Archive (EGA), which is hosted by the European Bioinformatics Institute (EBI) and the Centre for Genomic Regulation (CRG), ega-box-1210, under accession no. EGAS00001003622. [ABSTRACT FROM AUTHOR]

Aims/hypothesis: Gestational diabetes mellitus (GDM) affects 14% of all pregnancies worldwide and is associated with cardiometabolic risk. We aimed to exploit high-resolution wearable device time-series data to create a fine-grained physiological characterisation of the postpartum GDM state in free-living conditions, including clinical variables, daily glucose dynamics, food and drink consumption, physical activity, sleep patterns and heart rate., Methods: In a prospective observational study, we employed continuous glucose monitors (CGMs), a smartphone food diary, triaxial accelerometers and heart rate and heart rate variability monitors over a 2 week period to compare women who had GDM in the previous pregnancy (GDM group) and women who had a pregnancy with normal glucose metabolism (non-GDM group) at 1-2 months after delivery (baseline) and 6 months later (follow-up). We integrated CGM data with ingestion events recorded with the smartphone app MyFoodRepo to quantify the rapidity of returning to preprandial glucose levels after meal consumption. We inferred the properties of the underlying 24 h rhythm in the baseline glucose. Aggregating the baseline and follow-up data in a linear mixed model, we quantified the relationships between glycaemic variables and wearable device-derived markers of circadian timing., Results: Compared with the non-GDM group (n=15), the GDM group (n=22, including five with prediabetes defined based on fasting plasma glucose [5.6-6.9 mmol/l (100-125 mg/dl)] and/or HbA 1c [39-47 mmol/mol (5.7-6.4%)]) had a higher BMI, HbA 1c and mean amplitude of glycaemic excursion at baseline (all p≤0.05). Integrating CGM data and ingestion events showed that the GDM group had a slower postprandial glucose decrease (p=0.01) despite having a lower proportion of carbohydrate intake, similar mean glucose levels and a reduced amplitude of the underlying glucose 24 h rhythm (p=0.005). Differences in CGM-derived variables persisted when the five women with prediabetes were removed from the comparison. Longitudinal analysis from baseline to follow-up showed a significant increase in fasting plasma glucose across both groups. The CGM-derived metrics showed no differences from baseline to follow-up. Late circadian timing (i.e. sleep midpoint, eating midpoint and peak time of heart rate) was correlated with higher fasting plasma glucose and reduced amplitudes of the underlying glucose 24 h rhythm (all p≤0.05)., Conclusions/interpretation: We reveal GDM-related postpartum differences in glucose variability and 24 h rhythms, even among women clinically considered to be normoglycaemic. Our results provide a rationale for future interventions aimed at improving glucose variability and encouraging earlier daily behavioural patterns to mitigate the long-term cardiometabolic risk of GDM., Trial Registration: ClinicalTrials.gov no. NCT04642534., Competing Interests: Acknowledgements The authors wish to thank all participants and their families, the clinical team at the Maternity ward and Gestational Diabetes clinic, CHUV, the laboratory team at the Serum Biobank, CHUV, Y. Dibner at EPFL for the RedCap development, the Clinical Trial Unit at CHUV, the team at Digital Epidemiology laboratory, EPFL and the annotators of all recorded collected food and drink pictures via the MyFoodRepo app. Data availability The data are available upon reasonable request to the corresponding authors. Funding Open access funding provided by University of Geneva. This project was supported by the Leenaards Foundation (THC, JJP, CD), the Vontobel Foundation (THC, CD), the Swiss Life Jubiläumsstiftung Foundation (THC, FS), the Swiss Society of Endocrinology and Diabetes (THC, FS, NEP) and the Hjelt Foundation (NEP). THC’s research is supported by grants from the Swiss National Science Foundation (SNSF, PZ00P3-167826, 32003B-212559), the Nutrition 2000plus Foundation and the Medical Board of the Geneva University Hospitals. CD’s research is supported by SNSF grants 310030-184708 and 310030-219187, the Vontobel Foundation, the Olga Mayenfisch Foundation, Ligue Pulmonaire Genevoise, Swiss Cancer League (KFS-5266-02-2021-R), the Velux Foundation, the ISREC Foundation and the Gertrude von Meissner Foundation. JJP’s research is supported by SNSF grant 32003B-176119, the Gottfried und Julia Bangerter-Rhyner Foundation, an unrestricted educational grant from Novo Nordisk and a grant from the Dreyfus Foundation. Authors’ relationships and activities The authors declare that there are no relationships or activities that might bias, or be perceived to bias, their work. Contribution statement NEP, CD, JJP and THC conceptualised the study. NEP, CD, JJP and THC acquired funding. NEP, JM, ADB, FS, SU, FN, CD, JJP and THC developed and implemented the methodology. JM, SU, AH, JJP and THC collected the data. NEP, ADB, SB, FN, MS and THC analysed the data. NEP, MS and THC developed/worked on the software. NEP and THC created the visualisation. NEP and THC wrote the original draft manuscript. CD, JJP and THC performed supervision and project administration. All authors have read, edited and agreed to the published version of the manuscript. NEP, CD, JJP and THC are responsible for the integrity of the work as a whole., (© 2024. The Author(s).)

Aims/hypothesis: The circadian system plays an essential role in regulating the timing of human metabolism. Indeed, circadian misalignment is strongly associated with high rates of metabolic disorders. The properties of the circadian oscillator can be measured in cells cultured in vitro and these cellular rhythms are highly informative of the physiological circadian rhythm in vivo. We aimed to discover whether molecular properties of the circadian oscillator are altered as a result of type 2 diabetes., Methods: We assessed molecular clock properties in dermal fibroblasts established from skin biopsies taken from nine obese and eight non-obese individuals with type 2 diabetes and 11 non-diabetic control individuals. Following in vitro synchronisation, primary fibroblast cultures were subjected to continuous assessment of circadian bioluminescence profiles based on lentiviral luciferase reporters., Results: We observed a significant inverse correlation (ρ = -0.592; p < 0.05) between HbA 1c values and circadian period length within cells from the type 2 diabetes group. RNA sequencing analysis conducted on samples from this group revealed that ICAM1, encoding the endothelial adhesion protein, was differentially expressed in fibroblasts from individuals with poorly controlled vs well-controlled type 2 diabetes and its levels correlated with cellular period length. Consistent with this circadian link, the ICAM1 gene also displayed rhythmic binding of the circadian locomotor output cycles kaput (CLOCK) protein that correlated with gene expression., Conclusions/interpretation: We provide for the first time a potential molecular link between glycaemic control in individuals with type 2 diabetes and circadian clock machinery. This paves the way for further mechanistic understanding of circadian oscillator changes upon type 2 diabetes development in humans., Data Availability: RNA sequencing data and clinical phenotypic data have been deposited at the European Genome-phenome Archive (EGA), which is hosted by the European Bioinformatics Institute (EBI) and the Centre for Genomic Regulation (CRG), ega-box-1210, under accession no. EGAS00001003622.