Effects of different insulin sensitisers in the management of polycystic ovary syndrome: A systematic review and meta-analysis.

OBJECTIVE: Characteristic features of polycystic ovary syndrome (PCOS) include insulin resistance and an increased risk for type 2 diabetes. To promote improved insulin sensitivity, insulin sensitisers have been used in PCOS. However, direct comparisons across these agents are limited. This study compared the effects of metformin, rosiglitazone and pioglitazone in the management of PCOS to inform the 2023 International Evidence-based PCOS Guideline. DESIGN: Systematic review and meta-analysis of the literature. PATIENTS: Women with PCOS and treatment with insulin sensitisers. MEASUREMENTS: Hormonal and clinical outcomes, as well as side effects. RESULTS: Of 1660 publications identified, 13 randomised controlled trials were included. Metformin was superior in lowering weight (mean difference [MD]: -4.39, 95% confidence interval [CI]: -7.69 to -1.08 kg), body mass index (MD: -0.95, 95% CI: -1.41 to -0.49 kg/m2 ) and testosterone (MD: -0.10, 95% CI: -0.18 to -0.03 nmol/L) versus rosiglitazone, whereas there was no difference when comparing metformin to pioglitazone. Adding rosiglitazone or pioglitazone to metformin did not improve metabolic outcomes. However, rosiglitazone seemed superior to metformin in lowering lipid concentrations. CONCLUSIONS: Metformin should remain the first-line insulin sensitising treatment in adults with PCOS for the prevention and management of weight and metabolic features. The addition of thiazolidinediones appears to offer little benefit.

Maternal metabolic conditions as predictors of breastfeeding outcomes: Insights from an Australian cohort study.

INTRODUCTION: Breastfeeding represents an important opportunity to optimize health outcomes for both mother and infant, particularly in the context of maternal metabolic conditions such as diabetes and polycystic ovary syndrome. However, evidence suggests that women affected by these conditions breastfeed at reduced rates and durations. Our aim was to use the large, prospective, community-based Australian Longitudinal Study on Women's Health (ALSWH) to conduct an in-depth exploratory analysis of breastfeeding outcomes in Australian women affected by key maternal metabolic conditions. MATERIAL AND METHODS: Data from 12 920 pregnancies to 5605 women from the 1973-1978 birth cohort of the ALSWH were examined. Univariable and multivariable regression using generalized estimating equation models were applied to assess breastfeeding initiation and duration (outcome measures) in relation to key self-reported maternal metabolic diagnoses (pre-gestational type 1 and type 2 diabetes, gestational diabetes, and polycystic ovary syndrome; main explanatory variables). Key sociodemographic and clinical covariates were also considered. RESULTS: Results showed no significant association between specific maternal metabolic diagnoses (pre-gestational or gestational diabetes, or polycystic ovary syndrome) and breastfeeding outcomes. However, maternal body mass index emerged as a key predictor of suboptimal breastfeeding outcomes. Pregnancies affected by maternal obesity were associated with a 2.1-fold increase in the odds of not initiating breastfeeding, after adjusting for other key variables (95% CI 1.67 to 2.60, p < 0.01). Maternal overweight and obesity were, respectively, associated with an adjusted 1.4-fold (95% CI 1.20 to 1.55, p < 0.01) and 1.8-fold increase (95% CI 1.60 to 2.10, p < 0.01) in the odds of a breastfeeding duration less than 6 months. CONCLUSIONS: Maternal obesity, rather than any specific maternal metabolic condition, appears to be a key predictor of breastfeeding outcomes in Australian women.

Combined oral contraceptive pill compared with no medical treatment in the management of polycystic ovary syndrome: A systematic review.

OBJECTIVE: As part of the update of the International Evidence-Based Guidelines for the Assessment and Management of polycystic ovary syndrome (PCOS), a systematic review was performed to inform evidence-based recommendations. DESIGN: Systematic review. Only randomised controlled trial were included. PATIENTS: Women with PCOS; the use of combined oral contraceptive pills (COCP) was compared with no medical treatment. MEASUREMENTS: Outcomes were designed in collaboration with clinical experts, researchers, and consumers. Critical outcomes included hirsutism, irregular cycles, quality of life, body mass index (BMI), and weight. RESULTS: 1660 publications were identified, but only four studies were included. No studies could be combined for meta-analysis. COCP treatment improved cycle regularity compared with no medical treatment (100% vs. 0%, with low certainty of evidence). COCP showed no difference in improvement of hirsutism or BMI compared with placebo or lifestyle; a lower weight after COCP compared with no treatment (mean difference [MD] -8.0 (95% confidence interval, CI -11.67); -4.33 kg); and improvement in quality of life (MD 1.2 [95% CI 0.96]; 1.44), but these results were all very low certainty of evidence. CONCLUSION: Results show that COCP benefit cycle regulation, but other benefits or potential adverse effects were only identified with very low certainty of evidence. The COCP is frontline medical treatment in PCOS, but this is still based on established efficacy in the broader general population. Our results show that research in PCOS is seriously lacking and should be prioritised to capture core reproductive, metabolic and psychological outcomes important in PCOS.

Recommendations from the 2023 International Evidence-based Guideline for the Assessment and Management of Polycystic Ovary Syndrome†.

STUDY QUESTION: What is the recommended assessment and management of those with polycystic ovary syndrome (PCOS), based on the best available evidence, clinical expertise, and consumer preference? SUMMARY ANSWER: International evidence-based guidelines address prioritized questions and outcomes and include 254 recommendations and practice points, to promote consistent, evidence-based care and improve the experience and health outcomes in PCOS. WHAT IS KNOWN ALREADY: The 2018 International PCOS Guideline was independently evaluated as high quality and integrated multidisciplinary and consumer perspectives from six continents; it is now used in 196 countries and is widely cited. It was based on best available, but generally very low to low quality, evidence. It applied robust methodological processes and addressed shared priorities. The guideline transitioned from consensus based to evidence-based diagnostic criteria and enhanced accuracy of diagnosis, whilst promoting consistency of care. However, diagnosis is still delayed, the needs of those with PCOS are not being adequately met, evidence quality was low and evidence-practice gaps persist. STUDY DESIGN, SIZE, DURATION: The 2023 International Evidence-based Guideline update reengaged the 2018 network across professional societies and consumer organizations, with multidisciplinary experts and women with PCOS directly involved at all stages. Extensive evidence synthesis was completed. Appraisal of Guidelines for Research and Evaluation-II (AGREEII)-compliant processes were followed. The Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) framework was applied across evidence quality, feasibility, acceptability, cost, implementation and ultimately recommendation strength and diversity and inclusion were considered throughout. PARTICIPANTS/MATERIALS, SETTING, METHODS: This summary should be read in conjunction with the full Guideline for detailed participants and methods. Governance included a six-continent international advisory and management committee, five guideline development groups, and paediatric, consumer, and translation committees. Extensive consumer engagement and guideline experts informed the update scope and priorities. Engaged international society-nominated panels included paediatrics, endocrinology, gynaecology, primary care, reproductive endocrinology, obstetrics, psychiatry, psychology, dietetics, exercise physiology, obesity care, public health and other experts, alongside consumers, project management, evidence synthesis, statisticians and translation experts. Thirty-nine professional and consumer organizations covering 71 countries engaged in the process. Twenty meetings and five face-to-face forums over 12 months addressed 58 prioritized clinical questions involving 52 systematic and 3 narrative reviews. Evidence-based recommendations were developed and approved via consensus across five guideline panels, modified based on international feedback and peer review, independently reviewed for methodological rigour, and approved by the Australian Government National Health and Medical Research Council (NHMRC). MAIN RESULTS AND THE ROLE OF CHANCE: The evidence in the assessment and management of PCOS has generally improved in the past five years, but remains of low to moderate quality. The technical evidence report and analyses (∼6000 pages) underpins 77 evidence-based and 54 consensus recommendations, with 123 practice points. Key updates include: i) further refinement of individual diagnostic criteria, a simplified diagnostic algorithm and inclusion of anti-Müllerian hormone (AMH) levels as an alternative to ultrasound in adults only; ii) strengthening recognition of broader features of PCOS including metabolic risk factors, cardiovascular disease, sleep apnea, very high prevalence of psychological features, and high risk status for adverse outcomes during pregnancy; iii) emphasizing the poorly recognized, diverse burden of disease and the need for greater healthcare professional education, evidence-based patient information, improved models of care and shared decision making to improve patient experience, alongside greater research; iv) maintained emphasis on healthy lifestyle, emotional wellbeing and quality of life, with awareness and consideration of weight stigma; and v) emphasizing evidence-based medical therapy and cheaper and safer fertility management. LIMITATIONS, REASONS FOR CAUTION: Overall, recommendations are strengthened and evidence is improved, but remains generally low to moderate quality. Significantly greater research is now needed in this neglected, yet common condition. Regional health system variation was considered and acknowledged, with a further process for guideline and translation resource adaptation provided. WIDER IMPLICATIONS OF THE FINDINGS: The 2023 International Guideline for the Assessment and Management of PCOS provides clinicians and patients with clear advice on best practice, based on the best available evidence, expert multidisciplinary input and consumer preferences. Research recommendations have been generated and a comprehensive multifaceted dissemination and translation program supports the Guideline with an integrated evaluation program. STUDY FUNDING/COMPETING INTEREST(S): This effort was primarily funded by the Australian Government via the National Health Medical Research Council (NHMRC) (APP1171592), supported by a partnership with American Society for Reproductive Medicine, Endocrine Society, European Society for Human Reproduction and Embryology, and European Society for Endocrinology. The Commonwealth Government of Australia also supported Guideline translation through the Medical Research Future Fund (MRFCRI000266). HJT and AM are funded by NHMRC fellowships. JT is funded by a Royal Australasian College of Physicians (RACP) fellowship. Guideline development group members were volunteers. Travel expenses were covered by the partnering organizations. Disclosures of interest were strictly managed according to NHMRC policy and are available with the full guideline, technical evidence report, peer review and responses (www.monash.edu/medicine/mchri/pcos). Of named authors HJT, CTT, AD, LM, LR, JBoyle, AM have no conflicts of interest to declare. JL declares grant from Ferring and Merck; consulting fees from Ferring and Titus Health Care; speaker's fees from Ferring; unpaid consultancy for Ferring, Roche Diagnostics and Ansh Labs; and sits on advisory boards for Ferring, Roche Diagnostics, Ansh Labs, and Gedeon Richter. TP declares a grant from Roche; consulting fees from Gedeon Richter and Organon; speaker's fees from Gedeon Richter and Exeltis; travel support from Gedeon Richter and Exeltis; unpaid consultancy for Roche Diagnostics; and sits on advisory boards for Roche Diagnostics. MC declares travels support from Merck; and sits on an advisory board for Merck. JBoivin declares grants from Merck Serono Ltd.; consulting fees from Ferring B.V; speaker's fees from Ferring Arzneimittell GmbH; travel support from Organon; and sits on an advisory board for the Office of Health Economics. RJN has received speaker's fees from Merck and sits on an advisory board for Ferring. AJoham has received speaker's fees from Novo Nordisk and Boehringer Ingelheim. The guideline was peer reviewed by special interest groups across our 39 partner and collaborating organizations, was independently methodologically assessed against AGREEII criteria and was approved by all members of the guideline development groups and by the NHMRC.

Models Predicting Postpartum Glucose Intolerance Among Women with a History of Gestational Diabetes Mellitus: a Systematic Review.

PURPOSE OF REVIEW: Despite the crucial role that prediction models play in guiding early risk stratification and timely intervention to prevent type 2 diabetes after gestational diabetes mellitus (GDM), their use is not widespread in clinical practice. The purpose of this review is to examine the methodological characteristics and quality of existing prognostic models predicting postpartum glucose intolerance following GDM. RECENT FINDINGS: A systematic review was conducted on relevant risk prediction models, resulting in 15 eligible publications from research groups in various countries. Our review found that traditional statistical models were more common than machine learning models, and only two were assessed to have a low risk of bias. Seven were internally validated, but none were externally validated. Model discrimination and calibration were done in 13 and four studies, respectively. Various predictors were identified, including body mass index, fasting glucose concentration during pregnancy, maternal age, family history of diabetes, biochemical variables, oral glucose tolerance test, use of insulin in pregnancy, postnatal fasting glucose level, genetic risk factors, hemoglobin A1c, and weight. The existing prognostic models for glucose intolerance following GDM have various methodological shortcomings, with only a few models being assessed to have low risk of bias and validated internally. Future research should prioritize the development of robust, high-quality risk prediction models that follow appropriate guidelines, in order to advance this area and improve early risk stratification and intervention for glucose intolerance and type 2 diabetes among women who have had GDM.

Liver-expressed antimicrobial peptide 2 is associated with improved pancreatic insulin secretion in adults with overweight and obesity.

AIMS: To examine association of liver-expressed antimicrobial peptide 2 (LEAP2), an endogenous ghrelin antagonist with anorexiant effects, to key cardiometabolic risk factors in people with overweight and obesity. METHODS: In this cross-sectional study, we sought to identify associations between LEAP2 levels and cardiometabolic risk factors, including body composition (dual X-ray absorptiometry), insulin and glucose metabolism (oral and intravenous glucose tolerance tests and hyperinsulinaemic-euglycaemic clamps), plasma lipids and inflammation markers (ELISA and multiplex assays). RESULTS: In 65 participants with overweight or obesity (63.1% male, mean age 31.3 ± 8.5 years), LEAP2 levels were associated with total body fat, but not with body mass index or waist-hip ratio in both univariable and age- and sex-adjusted models (P < 0.05). Higher LEAP2 level was also positively associated with higher insulin secretion in univariable (P = 0.047) and multivariable models adjusted for age, sex and body fat (P = 0.03), but not with fasting glucose levels (P ≥ 0.05). Higher LEAP2 levels were associated insulin resistance (P = 0.07) after adjustment for age and sex, but the association disappeared after an additional adjustment for body fat (P = 0.2). There was an inverse association between LEAP2 levels and nuclear factor kappa-B (NFκB) activity in the peripheral blood mononuclear cells in age-, sex- and body fat-adjusted models (P = 0.04). There were no associations with cardiovascular risk factors (lipids, blood pressure) or other inflammation markers. CONCLUSIONS: These results provide important insights into the association between LEAP2 and cardiometabolic health in a high-risk population of individuals with overweight and obesity. This is a first report of an association between LEAP2 and insulin secretion, insulin sensitivity and NFκB activity. LEAP2 may represent an important potential therapeutic target to promote insulin secretion in people with type 2 diabetes and obesity.

Maternal diet quality and associations with plasma lipid profiles and pregnancy-related cardiometabolic health.

PURPOSE: To assess the relationship of early pregnancy maternal diet quality (DQ) with maternal plasma lipids and indicators of cardiometabolic health, including blood pressure (BP), gestational diabetes mellitus (GDM) and gestational weight gain (GWG). METHODS: Women (n = 215) aged 18-40 years with singleton pregnancies were recruited at 10-20 weeks gestation. Diet quality was assessed by the Dietary Guideline Index, calculated at early ([mean ± SD]) (15 ± 3 weeks) and late (35 ± 2 weeks) pregnancy. Lipidomic analysis was performed, and 698 species across 37 lipid classes were measured from plasma blood samples collected at early (15 ± 3 weeks) and mid (27 ± 3 weeks)-pregnancy. Clinical measures (BP, GDM diagnosis, weight) and blood samples were collected across pregnancy. Multiple linear and logistic regression models assessed associations of early pregnancy DQ with plasma lipids at early and mid-pregnancy, BP at three antenatal visits, GDM diagnosis and total GWG. RESULTS: Maternal DQ scores ([mean ± SD]) decreased significantly from early (70.7 ± 11.4) to late pregnancy (66.5 ± 12.6) (p < 0.0005). At a false discovery rate of 0.2, early pregnancy DQ was significantly associated with 13 plasma lipids at mid-pregnancy, including negative associations with six triglycerides (TGs); TG(54:0)[NL-18:0] (neutral loss), TG(50:1)[NL-14:0], TG(48:0)[NL-18:0], TG(52:1)[NL-18:0], TG(54:1)[NL-18:1], TG(50:0)[NL-18:0]. No statistically significant associations were found between early pregnancy DQ and BP, GDM or GWG. CONCLUSION: Maternal diet did not adhere to Australian Dietary Guidelines. Diet quality was inversely associated with multiple plasma TGs. This study provides novel insights into the relationship between DQ, lipid biomarkers and cardiometabolic health during pregnancy.

Lifestyle management in polycystic ovary syndrome - beyond diet and physical activity.

Polycystic ovary syndrome (PCOS) is a common condition affecting reproductive-aged women with reproductive, metabolic and psychological consequences. Weight and lifestyle (diet, physical activity and behavioural) management are first-line therapy in international evidence-based guidelines for PCOS. While these recommend following population-level diet and physical activity guidelines, there is ongoing interest and research in the potential benefit of including psychological and sleep interventions, as well as a range of traditional, complimentary and integrative medicine (TCIM) approaches, for optimal management of PCOS. There is limited evidence to recommend a specific diet composition for PCOS with approaches including modifying protein, carbohydrate or fat quality or quantity generally having similar effects on the presentations of PCOS. With regards to physical activity, promising evidence supports the provision of vigorous aerobic exercise, which has been shown to improve body composition, cardiorespiratory fitness and insulin resistance. Psychological and sleep interventions are also important considerations, with women displaying poor emotional wellbeing and higher rates of clinical and subclinical sleep disturbance, potentially limiting their ability to make positive lifestyle change. While optimising sleep and emotional wellbeing may aid symptom management in PCOS, research exploring the efficacy of clinical interventions is lacking. Uptake of TCIM approaches, in particular supplement and herbal medicine use, by women with PCOS is growing. However, there is currently insufficient evidence to support integration into routine clinical practice. Research investigating inositol supplementation have produced the most promising findings, showing improved metabolic profiles and reduced hyperandrogenism. Findings for other supplements, herbal medicines, acupuncture and yoga is so far inconsistent, and to reduce heterogeneity more research in specific PCOS populations, (e.g. defined age and BMI ranges) and consistent approaches to intervention delivery, duration and comparators are needed. While there are a range of lifestyle components in addition to population-recommendations for diet and physical activity of potential benefit in PCOS, robust clinical trials are warranted to expand the relatively limited evidence-base regarding holistic lifestyle management. With consumer interest in holistic healthcare rising, healthcare providers will be required to broaden their knowledge pertaining to how these therapies can be safely and appropriately utilised as adjuncts to conventional medical management.

Prolactin in Pregnancies Affected by Pre-Existing Maternal Metabolic Conditions: A Systematic Review.

Women affected by maternal pregestational diabetes mellitus (type 1 or type 2) or by polycystic ovary syndrome experience an increased risk of pregnancy complications, as well as suboptimal lactation outcomes. The hormone prolactin plays important roles in pregnancy and postpartum, both as a metabolic and lactogenic hormone. We aimed to explore, through a systematic review, the relationship between pregestational maternal metabolic conditions and prolactin levels in pregnancy and postpartum. MEDLINE via OVID, CINAHL Plus, and Embase were searched from inception to 9 May 2022. Eligible studies included women who were pregnant or up to 12 months postpartum and had a pre-existing diagnosis of type 1 or type 2 diabetes mellitus or polycystic ovary syndrome; with reporting of at least one endogenous maternal serum prolactin level during this time. Two independent reviewers extracted the data. Eleven studies met the eligibility criteria. The studies were too diverse and heterogeneous to enable meta-analysis. Overall, prolactin levels appeared to be lower in pregnancies affected by type 1 diabetes mellitus. There was little data in polycystic ovary syndrome or type 2 diabetes pregnancy, but prolactin increment across pregnancy in polycystic ovary syndrome emerged as an area for future study. During postpartum, lactation difficulties in women with metabolic disease present before pregnancy are well-described, but the relationship to prolactin remains unclear. Overall, preliminary evidence suggests that pre-existing maternal metabolic disease may alter prolactin dynamics in pregnancy and postpartum. Further well-designed studies in modern cohorts, with standardised collection and serial sampling across pregnancy and postpartum, are required to clarify these associations.

Strategic Design and Synthesis of Ferrocene Linked Porous Organic Frameworks toward Tunable CO2 Capture and Energy Storage.

This work focuses on porous organic polymers (POPs), which have gained significant global attention for their potential in energy storage and carbon dioxide (CO2) capture. The study introduces the development of two novel porous organic polymers, namely FEC-Mel and FEC-PBDT POPs, constructed using a simple method based on the ferrocene unit (FEC) combined with melamine (Mel) and 6,6'-(1,4-phenylene)bis(1,3,5-triazine-2,4-diamine) (PBDT). The synthesis involved the condensation reaction between ferrocenecarboxaldehyde monomer (FEC-CHO) and the respective aryl amines. Several analytical methods were employed to investigate the physical characteristics, chemical structure, morphology, and potential applications of these porous materials. Through thermogravimetric analysis (TGA), it was observed that both FEC-Mel and FEC-PBDT POPs exhibited exceptional thermal stability. FEC-Mel POP displayed a higher surface area and porosity, measuring 556 m2 g-1 and 1.26 cm3 g-1, respectively. These FEC-POPs possess large surface areas, making them promising materials for applications such as supercapacitor (SC) electrodes and gas adsorption. With 82 F g-1 of specific capacitance at 0.5 A g-1, the FEC-PBDT POP electrode has exceptional electrochemical characteristics. In addition, the FEC-Mel POP showed remarkable CO2 absorption capabilities, with 1.34 and 1.75 mmol g-1 (determined at 298 and 273 K; respectively). The potential of the FEC-POPs created in this work for CO2 capacity and electrical testing are highlighted by these results.

Rational Design of Bifunctional Microporous Organic Polymers Containing Anthracene and Triphenylamine Units for Energy Storage and Biological Applications.

In this study, we synthesized two conjugated microporous polymers (CMPs), An-Ph-TPA and An-Ph-Py CMPs, using the Suzuki cross-coupling reaction. These CMPs are organic polymers with p-conjugated skeletons and persistent micro-porosity and contain anthracene (An) moieties linked to triphenylamine (TPA) and pyrene (Py) units. We characterized the chemical structures, porosities, thermal stabilities, and morphologies of the newly synthesized An-CMPs using spectroscopic, microscopic, and N2 adsorption/desorption isotherm techniques. Our results from thermogravimetric analysis (TGA) showed that the An-Ph-TPA CMP displayed better thermal stability with Td10 = 467 °C and char yield of 57 wt% compared to the An-Ph-Py CMP with Td10 = 355 °C and char yield of 54 wt%. Furthermore, we evaluated the electrochemical performance of the An-linked CMPs and found that the An-Ph-TPA CMP had a higher capacitance of 116 F g-1 and better capacitance stability of 97% over 5000 cycles at 10 A g-1. In addition, we assessed the biocompatibility and cytotoxicity of An-linked CMPs using the MTT assay and a live/dead cell viability assay and observed that they were non-toxic and biocompatible with high cell viability values after 24 or 48 h of incubation. These findings suggest that the An-based CMPs synthesized in this study have potential applications in electrochemical testing and the biological field.

Design and Synthesis of Bisulfone-Linked Two-Dimensional Conjugated Microporous Polymers for CO2 Adsorption and Energy Storage.

We have successfully synthesized two types of two-dimensional conjugated microporous polymers (CMPs), Py-BSU and TBN-BSU CMPs, by using the Sonogashira cross-coupling reaction of BSU-Br2 (2,8-Dibromothianthrene-5,5',10,10'-Tetraoxide) with Py-T (1,3,6,8-Tetraethynylpyrene) and TBN-T (2,7,10,15-Tetraethynyldibenzo[g,p]chrysene), respectively. We characterized the chemical structure, morphology, physical properties, and potential applications of these materials using various analytical instruments. Both Py-BSU and TBN-BSU CMPs showed high thermal stability with thermal decomposition temperatures (Td10) up to 371 °C and char yields close to 48 wt%, as determined by thermogravimetric analysis (TGA). TBN-BSU CMPs exhibited a higher specific surface area and porosity of 391 m2 g-1 and 0.30 cm3 g-1, respectively, due to their large micropore and mesopore structure. These CMPs with extended π-conjugated frameworks and high surface areas are promising organic electroactive materials that can be used as electrode materials for supercapacitors (SCs) and gas adsorption. Our experimental results demonstrated that the TBN-BSU CMP electrode had better electrochemical characteristics with a longer discharge time course and a specific capacitance of 70 F g-1. Additionally, the electrode exhibited an excellent capacitance retention rate of 99.9% in the 2000-cycle stability test. The CO2 uptake capacity of TBN-BSU CMP and Py-BSU CMP were 1.60 and 1.45 mmol g-1, respectively, at 298 K and 1 bar. These results indicate that the BSU-based CMPs synthesized in this study have potential applications in electrical testing and CO2 capture.

Highly perturbed genes and hub genes associated with type 2 diabetes in different tissues of adult humans: a bioinformatics analytic workflow.

Type 2 diabetes (T2D) has a complex etiology which is not yet fully elucidated. The identification of gene perturbations and hub genes of T2D may deepen our understanding of its genetic basis. We aimed to identify highly perturbed genes and hub genes associated with T2D via an extensive bioinformatics analytic workflow consisting of five steps: systematic review of Gene Expression Omnibus and associated literature; identification and classification of differentially expressed genes (DEGs); identification of highly perturbed genes via meta-analysis; identification of hub genes via network analysis; and downstream analysis of highly perturbed genes and hub genes. Three meta-analytic strategies, random effects model, vote-counting approach, and p value combining approach, were applied. Hub genes were defined as those nodes having above-average betweenness, closeness, and degree in the network. Downstream analyses included gene ontologies, Kyoto Encyclopedia of Genes and Genomes pathways, metabolomics, COVID-19-related gene sets, and Genotype-Tissue Expression profiles. Analysis of 27 eligible microarrays identified 6284 DEGs (4592 downregulated and 1692 upregulated) in four tissue types. Tissue-specific gene expression was significantly greater than tissue non-specific (shared) gene expression. Analyses revealed 79 highly perturbed genes and 28 hub genes. Downstream analyses identified enrichments of shared genes with certain other diabetes phenotypes; insulin synthesis and action-related pathways and metabolomics; mechanistic associations with apoptosis and immunity-related pathways; COVID-19-related gene sets; and cell types demonstrating over- and under-expression of marker genes of T2D. Our approach provided valuable insights on T2D pathogenesis and pathophysiological manifestations. Broader utility of this pipeline beyond T2D is envisaged.

Maternal metabolic factors and the association with gestational diabetes: A systematic review and meta-analysis.

Gestational diabetes (GDM) is associated with several adverse outcomes for the mother and child. Higher levels of individual lipids are associated with risk of GDM and metabolic syndrome (MetS), a clustering of risk factors also increases risk for GDM. Metabolic factors can be modified by diet and lifestyle. This review comprehensively evaluates the association between MetS and its components, measured in early pregnancy, and risk for GDM. Databases (Cumulative Index to Nursing and Allied Health Literature, PubMed, Embase, and Cochrane Library) were searched from inception to 5 May 2021. Eligible studies included ≥1 metabolic factor (waist circumference, blood pressure, fasting plasma glucose (FPG), triglycerides, and high-density lipoprotein cholesterol), measured at <16 weeks' gestation. At least two authors independently screened potentially eligible studies. Heterogeneity was quantified using I2 . Data were pooled by random-effects models and expressed as odds ratio and 95% confidence intervals (CIs). Of 7213 articles identified, 40 unique articles were included in meta-analysis. In analyses adjusting for maternal age and body mass index, GDM was increased with increasing FPG (odds ratios [OR] 1.92; 95% CI 1.39-2.64, k = 7 studies) or having MetS (OR 2.52; 1.65, 3.84, k = 3). Women with overweight (OR 2.17; 95% CI 1.89, 2.50, k = 12) or obesity (OR 4.34; 95% CI 2.79-6.74, k = 9) also were at increased risk for GDM. Early pregnancy assessment of glucose or the MetS, offers a potential opportunity to detect and treat individual risk factors as an approach towards GDM prevention; weight loss for pregnant women with overweight or obesity is not recommended. Systematic review registration: PROSPERO CRD42020199225.

Human Placental Lactogen in Relation to Maternal Metabolic Health and Fetal Outcomes: A Systematic Review and Meta-Analysis.

Human placental lactogen (hPL) is a placental hormone which appears to have key metabolic functions in pregnancy. Preclinical studies have putatively linked hPL to maternal and fetal outcomes, yet-despite human observational data spanning several decades-evidence on the role and importance of this hormone remains disparate and conflicting. We aimed to explore (via systematic review and meta-analysis) the relationship between hPL levels, maternal pre-existing and gestational metabolic conditions, and fetal growth. MEDLINE via OVID, CINAHL plus, and Embase were searched from inception through 9 May 2022. Eligible studies included women who were pregnant or up to 12 months post-partum, and reported at least one endogenous maternal serum hPL level during pregnancy in relation to pre-specified metabolic outcomes. Two independent reviewers extracted data. Meta-analysis was conducted where possible; for other outcomes narrative synthesis was performed. 35 studies met eligibility criteria. No relationship was noted between hPL and gestational diabetes status. In type 1 diabetes mellitus, hPL levels appeared lower in early pregnancy (possibly reflecting delayed placental development) and higher in late pregnancy (possibly reflecting increased placental mass). Limited data were found in other pre-existing metabolic conditions. Levels of hPL appear to be positively related to placental mass and infant birthweight in pregnancies affected by maternal diabetes. The relationship between hPL, a purported pregnancy metabolic hormone, and maternal metabolism in human pregnancy is complex and remains unclear. This antenatal biomarker may offer value, but future studies in well-defined contemporary populations are required.

Providing lifestyle advice to women with PCOS: an overview of practical issues affecting success.

Polycystic Ovary Syndrome (PCOS) is a common endocrine disorder affecting up to 13 % of women. Lifestyle interventions are first-line treatments, however attrition in women with PCOS is high. This review summarises current evidence on barriers to lifestyle management in PCOS and suggested strategies for overcoming these challenges, mapped to the Capability, Opportunity, Motivation and Behaviour model.Physical capability for lifestyle changes may be impacted by altered gut hormone regulation and energy expenditure in PCOS. This may contribute to difficulties with weight management. The higher prevalence of eating disorders, disordered eating, fatigue and sleep disturbances are further barriers. Psychological capability may be reduced due psychological symptoms and lack of critical health literacy. Women with PCOS face similar challenges in terms of Opportunity to make lifestyle changes as other women of reproductive age. However, these are complicated by features more common in PCOS including body dissatisfaction. Motivation to adopt healthy lifestyles may be impacted by suboptimal risk perception and intrinsic motivation.To address these barriers, screening for and management of eating disorders, disordered eating, depression, and Obstructive Sleep Apnoea should be undertaken as per international evidence-based guidelines. A weight-neutral approach may be appropriate with disordered eating. Building capability among health professionals to better partner with women with PCOS on their management is essential in addressing health literacy gaps. Behavioural strategies that target risk perception and build intrinsic motivation should be utilised. More research is required to understand optimal self-management strategies, risk perception, energy homeostasis and overcoming attrition in women with PCOS.

Metabolomic Biomarkers in Gestational Diabetes Mellitus: A Review of the Evidence.

Gestational diabetes mellitus (GDM) is the fastest growing type of diabetes, affecting between 2 to 38% of pregnancies worldwide, varying considerably depending on diagnostic criteria used and sample population studied. Adverse obstetric outcomes include an increased risk of macrosomia, and higher rates of stillbirth, instrumental delivery, and birth trauma. Metabolomics, which is a platform used to analyse and characterise a large number of metabolites, is increasingly used to explore the pathophysiology of cardiometabolic conditions such as GDM. This review aims to summarise metabolomics studies in GDM (from inception to January 2021) in order to highlight prospective biomarkers for diagnosis, and to better understand the dysfunctional metabolic pathways underlying the condition. We found that the most commonly deranged pathways in GDM include amino acids (glutathione, alanine, valine, and serine), carbohydrates (2-hydroxybutyrate and 1,5-anhydroglucitol), and lipids (phosphatidylcholines and lysophosphatidylcholines). We also highlight the possibility of using certain metabolites as predictive markers for developing GDM, with the use of highly stratified modelling techniques. Limitations for metabolomic research are evaluated, and future directions for the field are suggested to aid in the integration of these findings into clinical practice.

Vitamin D and COVID-19: An Overview of Recent Evidence.

The novel coronavirus severe acute respiratory syndrome (SARS-CoV-2) has progressed rapidly from an outbreak to a global pandemic, with new variants rapidly emerging. Coronavirus disease 2019 (COVID-19), the disease resulting from SARS-CoV-2 infection, can lead to multiorgan damage. Due to the extremely contagious and fatal nature of the virus, it has been a priority of medical research to find effective means of treatment. Amid this search, the role of vitamin D in modulating various aspects of the innate and adaptive immune system has been discussed. This review aims to consolidate the research surrounding the role of vitamin D in the treatment and prevention of COVID-19. While there are some conflicting results reported, the consensus is that vitamin D has a host of immunomodulatory effects which may be beneficial in the context of COVID-19 and that low levels of vitamin D can result in dysfunction of crucial antimicrobial effects, potentially contributing to poor prognosis. Studies also show that the effects of low vitamin D can be mitigated via supplementation, although the benefits of vitamin D supplementation in the treatment of COVID-19 remain controversial.

Vitamin D supplementation increases adipokine concentrations in overweight or obese adults.

PURPOSE: Vitamin D regulates adipokine production in vitro; however, clinical trials have been inconclusive. We conducted secondary analyses of a randomized controlled trial to examine whether vitamin D supplementation improves adipokine concentrations in overweight/obese and vitamin D-deficient adults. METHODS: Sixty-five individuals with a BMI ≥ 25 kg/m2 and 25-hydroxyvitamin D (25(OH)D) ≤ 50 nmol/L were randomized to oral cholecalciferol (100,000 IU single bolus followed by 4,000 IU daily) or matching placebo for 16 weeks. We measured BMI, waist-to-hip ratio, % body fat (dual X-ray absorptiometry), serum 25(OH)D (chemiluminescent immunoassay) and total adiponectin, leptin, resistin, and adipsin concentrations (multiplex assay; flow cytometry). Sun exposure, physical activity, and diet were assessed using questionnaires. RESULTS: Fifty-four participants completed the study (35M/19F; mean age = 31.9 ± 8.5 years; BMI = 30.9 ± 4.4 kg/m2). After 16 weeks, vitamin D supplementation increased 25(OH)D concentrations compared with placebo (57.0 ± 21.3 versus 1.9 ± 15.1 nmol/L, p < 0.001). There were no differences between groups for changes in adiponectin, leptin, resistin, or adipsin in unadjusted analyses (all p > 0.05). After adjustment for baseline values, season, sun exposure, and dietary vitamin D intake, there was a greater increase in adiponectin (ß[95%CI] = 13.7[2.0, 25.5], p = 0.02) and leptin (ß[95%CI] = 22.3[3.8, 40.9], p = 0.02) in the vitamin D group compared with placebo. Results remained significant after additional adjustment for age, sex, and % body fat (p < 0.02). CONCLUSIONS: Vitamin D may increase adiponectin and leptin concentrations in overweight/obese and vitamin D-deficient adults. Further studies are needed to clarify the molecular interactions between vitamin D and adipokines and the clinical implications of these interactions in the context of obesity. CLINICAL TRIAL REGISTRATION: clinicaltrials.gov: NCT02112721.

Carnosine/histidine-containing dipeptide supplementation improves depression and quality of life: systematic review and meta-analysis of randomized controlled trials.

CONTEXT: Mental ill-health is a common and growing issue, affecting 1 in 8 individuals or 970 million people worldwide in 2019. Histidine-containing dipeptides (HCDs) have been suggested to mitigate some aspects of mental ill-health, but a quantitative synthesis of the evidence is lacking. Therefore, a systematic review and meta-analysis of randomized controlled trials was conducted. OBJECTIVE: To summarize the evidence on the effects of HCDs on mental health outcomes. DATA SOURCE: A systematic literature search was performed using electronic databases (Medline via Ovid, Embase via Ovid, Scopus, Google Scholar, and Cochrane) from inception to October, 2022. DATA EXTRACTION: Two authors independently extracted data using a structured extraction format. DATA ANALYSIS: Data analysis was performed using STATA version 17. Random-effects models were used, and heterogeneity was assessed using the I2 test. Quality appraisal was performed using the Cochrane risk-of-bias 2.0 tool and the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) approach. CONCLUSION: 5507 studies were identified, with 20 studies fulfilling the inclusion criteria. Eighteen studies comprising 776 participants were included in the meta-analysis. HCD supplementation (anserine/carnosine, l-carnosine, ß-alanine) caused a significant reduction in depression scores measured with the Becks Depression Inventory (-0.79; 95% CI: -1.24, -0.35; moderate certainty on GRADE) when compared with placebo. An increase in quality-of-life scores measured with the 36-item Short-Form survey (SF-36) (0.65; 95% CI: 0.00, 1.30) and low certainty on GRADE in HCDs (anserine/carnosine, l-carnosine, ß-alanine) when compared with placebo were found. However, the rest of the outcomes did not show a significant change between HCD supplementation and placebo. Although the number of studies included in the meta-analysis was modest, a significant mean reduction was observed in depression score as well as an increase in quality-of-life score for the HCD group when compared with placebo. Most of the studies included had small sample sizes with short follow-up periods and moderate to high risk of bias, highlighting the need for further, well-designed studies to improve the evidence base. SYSTEMATIC REVIEW REGISTRATION: PROSPERO registration no. CRD42017075354.