The metabolic and circadian signatures of gestational diabetes in the postpartum period characterised using multiple wearable devices.

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).

Alterations of lipid homeostasis in morbid obese patients are partly reversed by bariatric surgery.

Besides its beneficial effect on weight loss, gastric bypass surgery (GBS) may impact the circulating levels of phospho- and sphingolipids. However, long-term effects have not been explored. To investigate alterations in lipidomic signatures associated with massive weight loss following GBS, we conducted direct infusion tandem mass spectrometry on serum and subcutaneous adipose tissue (SAT) samples collected in a longitudinal cohort of morbid obese patients prior to GBS and 1 year following the surgery.

Circadian organization of lipid landscape is perturbed in type 2 diabetic patients.

Lipid homeostasis in humans follows a diurnal pattern in muscle and pancreatic islets, altered upon metabolic dysregulation. We employ tandem and liquid-chromatography mass spectrometry to investigate daily regulation of lipid metabolism in subcutaneous white adipose tissue (SAT) and serum of type 2 diabetic (T2D) and non-diabetic (ND) human volunteers (n = 12). Around 8% of ≈440 lipid metabolites exhibit diurnal rhythmicity in serum and SAT from ND and T2D subjects.

Lipid metabolism around the body clocks.

Lipids play important roles in energy metabolism along with diverse aspects of biological membrane structure, signaling and other functions. Perturbations of lipid metabolism are responsible for the development of various pathologies comprising metabolic syndrome, obesity, and type 2 diabetes. Accumulating evidence suggests that circadian oscillators, operative in most cells of our body, coordinate temporal aspects of lipid homeostasis.

Influence of circadian clocks on adaptive immunity and vaccination responses.

The adaptive immune response is under circadian control, yet, why adaptive immune reactions continue to exhibit circadian changes over long periods of time is unknown. Using a combination of experimental and mathematical modeling approaches, we show here that dendritic cells migrate from the skin to the draining lymph node in a time-of-day-dependent manner, which provides an enhanced likelihood for functional interactions with T cells. Rhythmic expression of TNF in the draining lymph node enhances BMAL1-controlled ICAM-1 expression in high endothelial venules, resulting in lymphocyte infiltration and lymph node expansion.

Type 2 diabetes disrupts circadian orchestration of lipid metabolism and membrane fluidity in human pancreatic islets.

Recent evidence suggests that circadian clocks ensure temporal orchestration of lipid homeostasis and play a role in pathophysiology of metabolic diseases in humans, including type 2 diabetes (T2D). Nevertheless, circadian regulation of lipid metabolism in human pancreatic islets has not been explored. Employing lipidomic analyses, we conducted temporal profiling in human pancreatic islets derived from 10 nondiabetic (ND) and 6 T2D donors.

Circulating 1,5-Anhydroglucitol as a Biomarker of ß-cell Mass Independent of a Diabetes Phenotype in Human Subjects.

Context: During an asymptomatic prediabetic state, the functional ß-cell mass decreases to a critical threshold, triggering diabetes and related symptoms. To date, there are no reliable readouts able to capture in vivo a potential drop of the ß-cell mass.

Objective: Beside its use as a short-term marker of glycemic control, the deoxyhexose 1,5-anhydroglucitol was identified in rodents as a circulating biomarker of the functional ß-cell mass already in the asymptomatic prediabetic stage.

Sex-specific modulation of circulating growth differentiation factor-15 in patients with type 2 diabetes and/or obesity.

Objective: Growth differentiation factor-15 (GDF15), a key metabolic regulator, is associated with obesity and diabetes in which sex-specific differences have been reported. Thus, we assessed whether GDF15 could be dependent on sex in diabetes and/or obesity groups.

Methods: We measured serum GDF15 levels by ELISA in eight lean women and men (n = 16), eight women and eight men having obesity (n = 16), eight women and eight men with type 2 diabetes (T2D, n = 16), and seven women and nine men with both diabetes and obesity (n = 16).

Recording of Diurnal Gene Expression in Peripheral Organs of Mice Using the RT-Biolumicorder.

There is high interest in investigating the daily dynamics of gene expression in mammalian organs, for example, in liver. Such studies help to elucidate how and with what kinetics peripheral clocks integrate circadian signals from the suprachiasmatic nucleus, which harbors the circadian master pacemaker, with other systemic and environmental cues, such as those associated with feeding and hormones. Organ sampling around the clock, followed by the analysis of RNA and/or proteins, is the most commonly used procedure in assessing rhythmic gene expression.

Circadian rhythm of lipid metabolism.

Lipids comprise a diverse group of metabolites that are indispensable as energy storage molecules, cellular membrane components and mediators of inter- and intra-cellular signaling processes. Lipid homeostasis plays a crucial role in maintaining metabolic health in mammals including human beings. A growing body of evidence suggests that the circadian clock system ensures temporal orchestration of lipid homeostasis, and that perturbation of such diurnal regulation leads to the development of metabolic disorders comprising obesity and type 2 diabetes.

Circadian clocks guide dendritic cells into skin lymphatics.

Migration of leukocytes from the skin to lymph nodes (LNs) via afferent lymphatic vessels (LVs) is pivotal for adaptive immune responses. Circadian rhythms have emerged as important regulators of leukocyte trafficking to LNs via the blood. Here, we demonstrate that dendritic cells (DCs) have a circadian migration pattern into LVs, which peaks during the rest phase in mice.

Circadian hepatocyte clocks keep synchrony in the absence of a master pacemaker in the suprachiasmatic nucleus or other extrahepatic clocks.

It has been assumed that the suprachiasmatic nucleus (SCN) synchronizes peripheral circadian oscillators. However, this has never been convincingly shown, since biochemical time series experiments are not feasible in behaviorally arrhythmic animals. By using long-term bioluminescence recording in freely moving mice, we show that the SCN is indeed required for maintaining synchrony between organs.

Ether lipids, sphingolipids and toxic 1-deoxyceramides as hallmarks for lean and obese type 2 diabetic patients.

Aim: The worldwide increase in obesity and type 2 diabetes (T2D) represents a major health challenge. Chronically altered lipids induced by obesity further promote the development of T2D, and the accumulation of toxic lipid metabolites in serum and peripheral organs may contribute to the diabetic phenotype.

Methods: To better understand the complex metabolic pattern of lean and obese T2D and non-T2D individuals, we analysed the lipid profile of human serum, skeletal muscle and visceral adipose tissue of two cohorts by systematic mass spectrometry-based lipid analysis.

Circadian Clocks Make Metabolism Run.

Most organisms adapt to the 24-h cycle of the Earth's rotation by anticipating the time of the day through light-dark cycles. The internal time-keeping system of the circadian clocks has been developed to ensure this anticipation. The circadian system governs the rhythmicity of nearly all physiological and behavioral processes in mammals.

Cellular circadian period length inversely correlates with HbA levels in individuals with type 2 diabetes.

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.

Diurnal Oscillations in Liver Mass and Cell Size Accompany Ribosome Assembly Cycles.

The liver plays a pivotal role in metabolism and xenobiotic detoxification, processes that must be particularly efficient when animals are active and feed. A major question is how the liver adapts to these diurnal changes in physiology. Here, we show that, in mice, liver mass, hepatocyte size, and protein levels follow a daily rhythm, whose amplitude depends on both feeding-fasting and light-dark cycles.

Clock-Talk: Interactions between Central and Peripheral Circadian Oscillators in Mammals.

In mammals, including humans, nearly all physiological processes are subject to daily oscillations that are governed by a circadian timing system with a complex hierarchical structure. The central pacemaker, residing in the suprachiasmatic nucleus (SCN) of the ventral hypothalamus, is synchronized daily by photic cues transmitted from the retina to SCN neurons via the retinohypothalamic tract. In turn, the SCN must establish phase coherence between self-sustained and cell-autonomous oscillators present in most peripheral cell types.

Cytoplasmic Control of Sense-Antisense mRNA Pairs.

Transcriptome analyses have revealed that convergent gene transcription can produce many 3'-overlapping mRNAs in diverse organisms. Few studies have examined the fate of 3'-complementary mRNAs in double-stranded RNA-dependent nuclear phenomena, and nothing is known about the cytoplasmic destiny of 3'-overlapping messengers or their impact on gene expression. Here, we demonstrate that the complementary tails of 3'-overlapping mRNAs can interact in the cytoplasm and promote post-transcriptional regulatory events including no-go decay (NGD) in Saccharomyces cerevisiae.

Activation of 5'-3' exoribonuclease Xrn1 by cofactor Dcs1 is essential for mitochondrial function in yeast.

The scavenger decapping enzyme Dcs1 has been shown to facilitate the activity of the cytoplasmic 5'-3' exoribonuclease Xrn1 in eukaryotes. Dcs1 has also been shown to be required for growth in glycerol medium. We therefore wondered whether the capacity to activate RNA degradation could account for its requirement for growth on this carbon source.

Real-time fluorescence detection of exoribonucleases.

The identification of RNases or RNase effectors is a continuous challenge, particularly given the current importance of RNAs in the control of genome expression. Here, we show that a fluorogenic RNA-DNA hybrid is a powerful tool for a real-time fluorescence detection and assay of exoribonucleases (RT-FeDEx). This RT-FeDEx assay provides a new strategy for the isolation, purification, and assay of known and unknown exoribonucleases.