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. The spectrum of rhythmic lipids differs between ND and T2D individuals, with the most substantial changes observed early morning, as confirmed by lipidomics in an independent cohort of ND and T2D subjects (n = 32) conducted at a single morning time point. Strikingly, metabolites identified as daily rhythmic in both serum and SAT from T2D subjects exhibit phase differences. Our study reveals massive temporal and tissue-specific alterations of human lipid homeostasis in T2D, providing essential clues for the development of lipid biomarkers in a temporal manner.

The impact of transsphenoidal surgery on pituitary function in patients with non-functioning macroadenomas.

PURPOSE: Transsphenoidal surgery for non-functioning pituitary adenomas (NFPAs) can alter pituitary function. We assessed the rates of improvement and deterioration of pituitary function by axis and searched for predictive factors of these outcomes. METHODS: We reviewed consecutive medical files from patients having had transsphenoidal surgery for NFPA between 2004 and 2018. Pituitary functions and MRI imaging were analyzed prior and after surgery. The occurrence of recovery and new deficit were documented per axis. Prognostic factors of hormonal recovery and new deficits were searched. RESULTS: Among 137 patients analyzed, median tumor size of the NFPA was 24.8 mm and 58.4% of patients presented visual impairment. Before surgery, 91 patients (67%) had at least one abnormal pituitary axis (hypogonadism: 62.4%; hypothyroidism: 41%, adrenal insufficiency: 30.8%, growth hormone deficiency: 29.9%; increased prolactin: 50.8%). Following surgery, the recovery rate of pituitary deficiency of one axis or more was 46% and the rate of new pituitary deficiency was 10%. Rates of LH-FSH, TSH, ACTH and GH deficiency recovery were 35.7%, 30.4%, 15.4%, and 45.5% respectively. Rates of new LH-FSH, TSH, ACTH and GH deficiencies were 8.3%, 1.6%, 9.2% and 5.1% respectively. Altogether, 24.6% of patients had a global pituitary function improvement and only 7% had pituitary function worsening after surgery. Male patients and patients with hyperprolactinemia upon diagnosis were more likely to experience pituitary function recovery. No prognostic factors for the risk of new deficiencies were identified. CONCLUSION: In a real-life cohort of patients with NFPAs, recovery of hypopituitarism after surgery is more frequent than the occurrence of new deficiencies. Hence, hypopituitarism could be considered a relative indication for surgery in patients with NFPAs.

A contemporary baseline of Madagascar's coral assemblages: Reefs with high coral diversity, abundance, and function associated with marine protected areas.

Madagascar is a major hotspot of biodiversity in the Western Indian Ocean, but, as in many other regions, coral reefs surrounding the island confront large-scale disturbances and human-induced local stressors. Conservation actions have been implemented with encouraging results for fisheries, though their benefit on coral assemblages has never been rigorously addressed. In this context, we analyzed the multiscale spatial variation of the composition, generic richness, abundance, life history strategies, and cover of coral assemblages among 18 stations placed at three regions around the island. The potential influences of marine protected areas (MPAs), algal cover, substrate rugosity, herbivorous fish biomass, and geographic location were also analyzed. Our results highlight the marked spatial variability, with variation at either or both regional and local scales for all coral descriptors. The northeast coastal region of Masoala was characterized by the high abundance of coral colonies, most notably of the competitive Acropora and Pocillopora genera and stress-tolerant taxa at several stations. The southwest station of Salary Nord was distinguished by lower abundances, with depauperate populations of competitive taxa. On the northwest coast, Nosy-Be was characterized by higher diversity and abundance as well as by high coral cover (~42-70%) recorded at unfished stations. Results clearly underline the positive effects of MPAs on all but one of the coral descriptors, particularly at Nosy-Be where the highest contrast between fished and unfished stations was observed. Biomass of herbivorous fishes, crustose coralline algae cover, and substrate rugosity were also positively related to several coral descriptors. The occurrence of reefs with high diversity, abundance, and cover of corals, including the competitive Acropora, is a major finding of this study. Our results strongly support the implementation of locally managed marine areas with strong involvement by primary users, particularly to assist in management in countries with reduced logistic and human resources such as Madagascar.

Moderate to Severe Soft Tissue Diabetic Foot Infections: A Randomized, Controlled, Pilot Trial of Post-debridement Antibiotic Treatment for 10 versus 20 days.

BACKGROUND: The optimal duration of antibiotic therapy for soft-tissue infections of the diabetic foot remains unknown. OBJECTIVE: We determine if antibiotic therapy after debridement for a short (10 days), compared with a long (20 days), duration for soft-tissue infections of the diabetic foot results in similar rates of clinical remission and adverse events (AE). SUMMARY OF BACKGROUND DATA: The optimal duration of systemic antibiotic therapy, after successful debridement, for soft tissue infections of diabetic patients is unknown. Because of the high recurrence risk, overuse is commonplace. METHODS: This was a randomized, controlled, non-inferiority pilot trial of cases of diabetic foot infection (excluding osteomyelitis) with the primary outcome of "clinical remission at 2-months follow-up". RESULTS: Among 66 enrolled episodes (17% females; median age 71 years), we randomized 35 to the 10-day arm and 31 to the 20-day arm. The median duration of the parenteral antibiotic therapy was 1 day, with the remainder given orally. In the intention-to-treat population, we achieved clinical remission in 27 (77%) patients in the 10-day arm compared to 22 (71%) in the 20-days arm ( P = 0.57). There were a similar proportion in each arm of AE (14/35 versus 11/31; P = 0.71), and remission in the per-protocol population (25/32 vs 18/27; P = 0.32). Overall, 8 soft tissue DFIs in the 10-day arm and 5 cases in the 20-day arm recurred as a new osteomyelitis [8/35 (23%) versus 5/31 (16%); P = 0.53]. Overall, the number of recurrences limited to the soft tissues was 4 (6%). By multivariate analysis, rates of remission (intention-to-treat population, hazard ratio 0.6, 95%CI 0.3-1.1; per-protocol population 0.8, 95%CI 0.4-1.5) and AE were not significantly different with a 10-day compared to 20-day course. CONCLUSIONS: In this randomized, controlled pilot trial, post-debridement antibiotic therapy for soft tissue DFI for 10 days gave similar (and non-inferior) rates of remission and AEs to 20 days. A larger confirmatory trial is under way. TRIAL REGISTRATION: ClinicalTrials NCT03615807.

Growth differentiation factor-15 prevents glucotoxicity and connexin-36 downregulation in pancreatic beta-cells.

Pancreatic beta cell dysfunction is a hallmark of type 2 diabetes. Growth differentiation factor 15 (GDF15), which is an energy homeostasis regulator, has been shown to improve several metabolic parameters in the context of diabetes. However, its effects on pancreatic beta-cell remain to be identified. We, therefore, performed experiments using cell models and histological sectioning of wild-type and knock-out GDF15 mice to determine the effect of GDF15 on insulin secretion and cell viability. A bioinformatics analysis was performed to identify GDF15-correlated genes. GDF15 prevents glucotoxicity-mediated altered glucose-stimulated insulin secretion (GSIS) and connexin-36 downregulation. Inhibition of endogenous GDF15 reduced GSIS in cultured mouse beta-cells under standard conditions while it had no impact on GSIS in cells exposed to glucolipotoxicity, which is a diabetogenic condition. Furthermore, this inhibition exacerbated glucolipotoxicity-reduced cell survival. This suggests that endogenous GDF15 in beta-cell is required for cell survival but not GSIS in the context of glucolipotoxicity.

Sphingosine-1-phosphate as a key player of insulin secretion induced by high-density lipoprotein treatment.

Beta cell failure is one of the most important features of type 2 diabetes mellitus (T2DM). High-density lipoprotein (HDL) has been proposed to improve ß-cell function. However, the mechanisms involved in this process are still poorly understood. The aim of this study was to investigate the contribution of sphingosine-1-phosphate (S1P) in the impact of HDL treatment on insulin secretion by pancreatic ß-cells and to determine its mechanisms. Primary cultures of ß-cells isolated from rat were treated with or without HDL in the presence or absence of S1P pathway inhibitors and insulin secretion response was analyzed. The S1P content of HDL (HDL-S1P) isolated from T2DM patients was analyzed and correlated to the HDL-induced insulin secretion. The expression of genes involved in the biosynthesis of the insulin was also evaluated. HDL as well as S1P treatment enhanced glucose-stimulated insulin secretion (GSIS). In HDL isolated from T2DM patients, while HDL-S1P was strongly correlated to its pro-secretory capacity (r = 0.633, p = 0.005), HDL-cholesterol and apolipoprotein AI levels were not. HDL-induced GSIS was blocked by the S1P1/3 antagonist but not by the S1P2 antagonist, and was also accompanied by increased intracellular S1P in ß-cells. We also observed that HDL improved GSIS without significant changes in expression levels of insulin biosynthesis genes. Our present study highlights the importance HDL-S1P in GSIS in T2DM patients and demonstrates that HDL induces insulin secretion by a process involving both intra- and extra-cellular sources of S1P independently of an effect on insulin biosynthesis genes.

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. RESULTS: Lipid homeostasis was strongly altered in a disease- and tissue-specific manner, allowing us to define T2D signatures associated with obesity from those that were obesity independent. Lipid changes encompassed lyso-, diacyl- and ether-phospholipids. Moreover, strong changes in sphingolipids included cytotoxic 1-deoxyceramide accumulation in a disease-specific manner in serum and visceral adipose tissue. The high amounts of non-canonical 1-deoxyceramide present in human adipose tissue most likely come from cell-autonomous synthesis because 1-deoxyceramide production increased upon differentiation to adipocytes in mouse cell culture experiments. CONCLUSION: Taken together, the observed lipidome changes in obesity and T2D will facilitate the identification of T2D patient subgroups and represent an important step towards personalized medicine in diabetes.

Three Weeks Versus Six Weeks of Antibiotic Therapy for Diabetic Foot Osteomyelitis: A Prospective, Randomized, Noninferiority Pilot Trial.

BACKGROUND: In patients with diabetic foot osteomyelitis (DFO) who underwent surgical debridement, we investigated whether a short (3 weeks) duration compared with a long (6 weeks) duration of systemic antibiotic treatment is associated with noninferior results for clinical remission and adverse events (AEs). METHODS: In this prospective, randomized, noninferiority pilot trial, we randomized (allocation 1:1) patients with DFO after surgical debridement to either a 3-week or a 6-week course of antibiotic therapy. The minimal duration of follow-up after the end of therapy was 2 months. We compared outcomes using Cox regression and noninferiority analyses (25% margin, power 80%). RESULTS: Among 93 enrolled patients (18% females; median age 65 years), 44 were randomized to the 3-week arm and 49 to the 6-week arm. The median number of surgical debridements was 1 (range, 0-2 interventions). In the intention-to-treat (ITT) population, remission occurred in 37 (84%) of the patients in the 3-week arm compared with 36 (73%) in the 6-week arm (P = .21). The number of AEs was similar in the 2 study arms (17/44 vs 16/49; P = .51), as were the remission incidences in the per-protocol (PP) population (33/39 vs 32/43; P = .26). In multivariate analysis, treatment with the shorter antibiotic course was not significantly associated with remission (ITT population: hazard ratio [HR], 1.1 [95% confidence interval {CI}, .6-1.7]; PP population: HR, 0.8 [95% CI: .5-1.4]). CONCLUSIONS: In this randomized controlled pilot trial, a postdebridement systemic antibiotic therapy course for DFO of 3 weeks gave similar (and statistically noninferior) incidences of remission and AE to a course of 6 weeks. CLINICAL TRIALS REGISTRATION: NCT03615807; BASEC 2016-01008 (Switzerland).

Let-7e-5p Regulates GLP-1 Content and Basal Release From Enteroendocrine L Cells From DIO Male Mice.

Characterization of enteroendocrine L cells in diabetes is critical for better understanding of the role of glucagon-like peptide-1 (GLP-1) in physiology and diabetes. We studied L-cell transcriptome changes including microRNA (miRNA) dysregulation in obesity and diabetes. We evaluated the regulation of miRNAs through microarray analyses on sorted enteroendocrine L cells from control and obese glucose-intolerant (I-HFD) and hyperglycemic (H-HFD) mice after 16 weeks of respectively low-fat diet (LFD) or high-fat diet (HFD) feeding. The identified altered miRNAs were studied in vitro using the mouse GLUTag cell line to investigate their regulation and potential biological functions. We identified that let-7e-5p, miR-126a-3p, and miR-125a-5p were differentially regulated in L cells of obese HFD mice compared with control LFD mice. While downregulation of let-7e-5p expression was observed in both I-HFD and H-HFD mice, levels of miR-126a-3p increased and of miR-125a-5p decreased significantly only in I-HFD mice compared with controls. Using miRNA inhibitors and mimics we observed that modulation of let-7e-5p expression affected specifically GLP-1 cellular content and basal release, whereas Gcg gene expression and acute GLP-1 secretion and cell proliferation were not affected. In addition, palmitate treatment resulted in a decrease of let-7e-5p expression along with an increase in GLP-1 content and release, suggesting that palmitate acts on GLP-1 through let-7e-5p. By contrast, modulation of miR-125a-5p and miR-126a-3p in the same conditions did not affect content or secretion of GLP-1. We conclude that decrease of let-7e-5p expression in response to palmitate may constitute a compensatory mechanism contributing to maintaining constant glycemia in obese mice.

Association between polycystic ovary syndrome and venous thromboembolism: A systematic review and meta-analysis.

AIMS: Polycystic ovary syndrome (PCOS) is very prevalent and commonly treated with prothrombotic combined oral contraceptives (COC). Our aim was to systematically review the available evidence to evaluate the risk of venous thromboembolism (VTE) associated with PCOS, and whether observed increased risks may be explained by a higher prevalence of obesity and hormonal treatments. METHOD: For this systematic review and meta-analysis, two authors independently searched MEDLINE, EMBASE and conference proceedings (ISTH, WHITH) from inception through 4.2019 for studies reporting the association of PCOS with VTE risk. Study quality was assessed and relative risk estimates were pooled through random effect models. RESULTS: We identified 5 large observational studies published between 2004 and 2018, most commonly using administrative data, set in Denmark, the USA or the United Kingdom. Compared with participants without PCOS, participants with PCOS had greater risks of VTE in unadjusted analyses (pooled OR 1.70, 95%CI 1.42-2.04, I2 67%). In three studies reporting analyses adjusted for at least obesity and hormonal treatments, PCOS was still associated with greater risks of VTE (pooled OR 1.89, 95%CI 1.60-2.24, I2 27%). CONCLUSIONS: PCOS appears to be a risk factor for VTE, independently of its associated excess weight and greater use of combined oral contraceptives. This should be taken into account in the pharmacological management of PCOS.

Validation of molecular biomarkers for preoperative diagnostics of human papillary thyroid carcinoma in fine needle aspirates.

BACKGROUND: Despite substantial efforts, reliable preoperative diagnostic for human thyroid malignancies in case of cytologically indeterminate nodules is still missing, resulting in high number of unnecessary thyroidectomies. In an attempt to increase precision of existing preoperative diagnostics, we aimed at validating the panel of molecular biomarkers predictive for papillary thyroid carcinoma (PTC) in preoperative fine needle aspirate (FNA) samples. METHODS: In this prospective study conducted in preoperative thyroid FNA from 44 thyroid nodules, expression levels of 11 molecular biomarkers previously validated on the postoperative samples of PTCs were measured by Cell-to-CT and QuantiGene Plex methods and correlated with final diagnosis. RESULTS: The QuantiGene Plex resulted in reliable gene expression measurements for FNA and core-needle biopsy (CNB) samples, however this method was less sensitive than pre-amplification based Cell-to-CT. Measurements conducted on the same samples by the two methods significantly correlated for most of the genes. Expression levels of TIMP1, c-MET and ARNTL were upregulated in PTC nodules as compared to benign counterparts, supporting previous post-operative studies. Strong correlation was observed between these biomarker alterations in the same samples. Within the sub-group of 15 indeterminate nodules (Bethesda II-V), TIMP1 had 100% specificity and 83% sensitivity for PTC cases. CONCLUSIONS: Assessment of TIMP1, c-MET and core-clock gene ARNTL expression levels by QuantiGene Plex assay in FNA samples holds promise as an ancillary method to the cytological preoperative diagnostics.

[GLP-1 analogues in 2019†: for whom and how ?] / Analogues du GLP-1 en 2019†: pour qui et comment ?

GLP-1 analogues are a well-established treatment for type 2 diabetes. They act by improving glycemic control through several mechanisms. They also have the advantage of inducing weight loss without the risk of associated hypoglycemia. This class of molecules has also shown a benefit in cardiovascular events such as cardiovascular mortality, stroke and myocardial infarction, and albuminuria. These favorable effects place them, like SGLT-2 inhibitors, as a second option in the case of unsatisfactory glycemic control after metformin and dietary and lifestyle measures. This article provides an overview of the current knowledge of GLP-1 analogue therapy in patients with type 2 diabetes.

Les analogues du GLP-1 constituent un traitement bien établi du diabète de type 2 en permettant une amélioration du contrôle glycémique au travers de plusieurs mécanismes. Ils possèdent également comme avantage l'induction d'une perte de poids sans risque d'hypoglycémie associée. Cette classe de molécules a aussi montré un bénéfice sur les événements cardiovasculaires tels que la mortalité cardiovasculaire, la survenue d'AVC et d'infarctus du myocarde et l'albuminurie. Ces effets favorables les placent, comme les inhibiteurs du SGLT-2, en deuxième option en cas de contrôle glycémique non satisfaisant après la metformine et les mesures hygiéno-diététiques. Cet article fait un survol des connaissances actuelles du traitement par analogues du GLP-1 chez les patients avec un diabète de type 2.

Cellular circadian period length inversely correlates with HbA1c 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. 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.

The Role of Sexual Hormones on the Enteroinsular Axis.

Sex steroid estrogens, androgens, and progesterone, produced by the gonads, which have long been considered as endocrine glands, are implicated in sexual differentiation, puberty, and reproduction. However, the impact of sex hormones goes beyond these effects through their role on energy metabolism. Indeed, sex hormones are important physiological regulators of glucose homeostasis and, in particular, of the enteroinsular axis. In this review, we describe the roles of estrogens, androgens, and progesterone on glucose homeostasis through their effects on pancreatic α- and ß-cells, as well as on enteroendocrine L-cells, and their implications in hormonal biosynthesis and secretion. The analysis of their mechanisms of action with the dissection of the receptors implicated in the several protective effects could provide some new aspects of the fine-tuning of hormonal secretion under the influence of the sex. This knowledge paves the way to the understanding of transgender physiology and new potential therapeutics in the field of type 2 diabetes.

High-fat diet impacts more changes in beta-cell compared to alpha-cell transcriptome.

Characterization of endocrine-cell functions and associated molecular signatures in diabetes is crucial to better understand why and by which mechanisms alpha and beta cells cause and perpetuate metabolic abnormalities. The now recognized role of glucagon in diabetes control is a major incentive to have a better understanding of dysfunctional alpha cells. To characterize molecular alterations of alpha cells in diabetes, we analyzed alpha-cell transcriptome from control and diabetic mice using diet-induced obesity model. To this aim, we quantified the expression levels of total mRNAs from sorted alpha and beta cells of low-fat and high-fat diet-treated mice through RNAseq experiments, using a transgenic mouse strain allowing collections of pancreatic alpha- and beta-cells after 16 weeks of diet. We now report that pancreatic alpha cells from obese hyperglycemic mice displayed minor variations of their transcriptome compared to controls. Depending on analyses, we identified 11 to 39 differentially expressed genes including non-alpha cell markers mainly due to minor cell contamination during purification process. From these analyses, we identified three new target genes altered in diabetic alpha cells and potently involved in cellular stress and exocytosis (Upk3a, Adcy1 and Dpp6). By contrast, analysis of the beta-cell transcriptome from control and diabetic mice revealed major alterations of specific genes coding for proteins involved in proliferation and secretion. We conclude that alpha cell transcriptome is less reactive to HFD diet compared to beta cells and display adaptations to cellular stress and exocytosis.

miR-132-3p is a positive regulator of alpha-cell mass and is downregulated in obese hyperglycemic mice.

OBJECTIVE: Diabetes is a complex disease implicating several organs and cell types. Within the islets, dysregulation occurs in both alpha- and beta-cells, leading to defects of insulin secretion and increased glucagon secretion. Dysregulation of alpha-cells is associated with transcriptome changes. We hypothesized that microRNAs (miRNAs) which are negative regulators of mRNA stability and translation could be involved in alpha-cell alterations or adaptations during type 2 diabetes. METHODS: miRNA microarray analyses were performed on pure alpha- and beta-cells from high-fat diet fed obese hyperglycemic mice and low-fat diet fed controls. Then, the most regulated miRNA was overexpressed or inhibited in primary culture of mouse and human alpha-cells to determine its molecular and functional impact. RESULTS: 16 miRNAs were significantly regulated in alpha-cells of obese hyperglycemic mice and 28 in beta-cells. miR-132-3p had the strongest regulation level in alpha-cells, where it was downregulated, while we observed an opposite upregulation in beta-cells. In vitro experiments showed that miR-132-3p, which is inversely regulated by somatostatin and cAMP, is a positive modulator of alpha-cell proliferation and implicated in their resistance to apoptosis. These effects are associated with the regulation of a series of genes, including proliferation and stress markers Mki67 and Bbc3 in mouse and human alpha-cells, potentially involved in miR-132-3p functions. CONCLUSIONS: Downregulation of miR-132-3p in alpha-cells of obese diabetic mice may constitute a compensatory mechanism contributing to keep glucagon-producing cell number constant in diabetes.

Consequences of the Adoption of the IADPSG versus Carpenter and Coustan Criteria to Diagnose Gestational Diabetes: A Before-After Comparison.

AIMS: To evaluate if the adoption of the International Association of Diabetes and Pregnancy Study Groups (IADPSG) diagnostic criteria for Gestational Diabetes Mellitus (GDM) led to changes in the management and in the occurrence of pregnancy complications. METHODS: This was a retrospective study of women with GDM followed at a single university center, diagnosed in 2009-2010 using the Carpenter and Coustan criteria (period 1) and in 2012-2013 using the IADPSG criteria (period 2). RESULTS: We included 286 women with GDM, 129 in period 1 and 157 in period 2. Age, body mass index and weight gain during pregnancy were similar. There were less women requiring insulin therapy in period 2 than in period 1 (43.3% versus 55.0% respectively, p=0.048), but no significant difference in the number of cesarean section, in babies born large for gestational age and in the occurrence of preeclampsia. There was less neonatal hypoglycemia (<2.5 mmol/l) in period 2 versus period 1 (7 versus 23 neonates respectively, p<0.001). CONCLUSIONS: When using the new IADPSG criteria, women with a less severe GDM are diagnosed, and fewer women require insulin. There was no difference in maternal outcomes, but less neonatal hypoglycemia during when using the IADPSG criteria.

Time zones of pancreatic islet metabolism.

Most living beings possess an intrinsic system of circadian oscillators, allowing anticipation of the Earth's rotation around its own axis. The mammalian circadian timing system orchestrates nearly all aspects of physiology and behaviour. Together with systemic signals originating from the central clock that resides in the hypothalamic suprachiasmatic nucleus, peripheral oscillators orchestrate tissue-specific fluctuations in gene transcription and translation, and posttranslational modifications, driving overt rhythms in physiology and behaviour. There is accumulating evidence of a reciprocal connection between the circadian oscillator and most aspects of physiology and metabolism, in particular as the circadian system plays a critical role in orchestrating body glucose homeostasis. Recent reports imply that circadian clocks operative in the endocrine pancreas regulate insulin secretion, and that islet clock perturbation in rodents leads to the development of overt type 2 diabetes. While whole islet clocks have been extensively studied during the last years, the heterogeneity of islet cell oscillators and the interplay between α- and ß-cellular clocks for orchestrating glucagon and insulin secretion have only recently gained attention. Here, we review recent findings on the molecular makeup of the circadian clocks operative in pancreatic islet cells in rodents and in humans, and focus on the physiologically relevant synchronizers that are resetting these time-keepers. Moreover, the implication of islet clock functional outputs in the temporal coordination of metabolism in health and disease will be highlighted.