Metabolic changes with intermittent fasting.

BACKGROUND: The prevalence of obesity is rising globally and effective strategies to treat obesity are needed. Intermittent fasting, a dietary intervention for weight management, has received growing interest from the general public, as well as healthcare professionals, as a form of lifestyle intervention. METHODS: We executed a rapid review using PUBMED database to identify systematic reviews that examined the impact of intermittent fasting on metabolic indices, published between 2011 and 2022. RESULTS: Intermittent fasting leads to weight loss of a similar magnitude to continuous energy restriction. Most of the evidence shows that intermittent fasting leads to greater fat loss as measured by fat mass (kg) or body fat percentage compared to an ad libitum diet, but fat loss attained during intermittent fasting is not significantly different to continuous energy restriction, although recent evidence shows intermittent fasting to be superior. There is mixed evidence for the impact of intermittent fasting on insulin resistance, fasting glucose and lipid profile. Some studies focused on populations of Muslim people, which showed that Ramadan fasting may lead to weight loss and improvement of metabolic parameters during fasting, although the effects are reversed when fasting is finished. CONCLUSIONS: Intermittent fasting is more effective than an ad libitum dietary intake, and equally or more effective as continuous energy restriction, for weight management. However, there is inconclusive evidence on whether intermittent fasting has a clinically beneficial effect on glucose and lipid metabolism.

Health Outcomes Following Engagement With a Digital Health Tool Among People With Prediabetes and Type 2 Diabetes: Prospective Evaluation Study.

BACKGROUND: Diabetes is a worldwide chronic condition causing morbidity and mortality, with a growing economic burden on health care systems. Complications from poorly controlled diabetes are associated with increased socioeconomic costs and reduced quality of life. Smartphones have become an influential platform, providing feasible tools such as health apps to deliver tailored support to enhance the ability of patients with diabetes for self-management. Gro Health is a National Health Service division X-certified digital health tool used to deliver educational and monitoring support to facilitate the development of skills and practices for maintaining good health. OBJECTIVE: This study aims to assess self-reported outcomes of the Gro Health app among users with diabetes and prediabetes and identify the factors that determine engagement with the digital health tool. METHODS: This was a service evaluation of self-reported data collected prospectively by the developers of the Gro Health app. The EQ-5D questionnaire is a standardized tool used to measure health status for clinical and economic appraisal. Gro Health users completed the EQ-5D at baseline and 6 months after using the app. Users provided informed consent for the use of their anonymized data for research purposes. EQ-5D index scores and visual analogue scale (VAS) scores were calculated at baseline and 6 months for individuals with prediabetes and type 2 diabetes. Descriptive statistics and multiple-regression models were used to assess changes in the outcome measures and determine factors that affected engagement with the digital tool. RESULTS: A total of 84% (1767/2114) of Gro Health participants completed EQ-5D at baseline and 6 months. EQ-5D index scores are average values that reflect people's preferences about their health state (1=full health and 0=moribund). There was a significant and clinically meaningful increase in mean EQ-5D index scores among app users between baseline (0.746, SD 0.23) and follow-up (0.792, SD 0.22; P<.001). The greatest change was observed in the mean VAS score, with a percentage change of 18.3% improvement (61.7, SD 18.1 at baseline; 73.0, SD 18.8 at follow-up; P<.001). Baseline EQ-5D index scores, age, and completion of educational modules were associated with significant changes in the follow-up EQ-5D index scores, with baseline EQ-5D index scores, race and ethnicity, and completion of educational modules being significantly associated with app engagement (P<.001). CONCLUSIONS: This study provides evidence of a significant positive effect on self-reported quality of life among people living with type 2 diabetes engaging with a digital health intervention. The improvements, as demonstrated by the EQ-5D questionnaire, are facilitated through access to education and monitoring support tools within the app. This provides an opportunity for health care professionals to incorporate National Health Service-certified digital tools, such as Gro Health, as part of the holistic management of people living with diabetes.

The Effects of the Mediterranean Diet on Health and Gut Microbiota.

The Mediterranean Diet (MD) is plant-based and consists of multiple daily portions of vegetables, fruit, cereals, and olive oil. Although there are challenges with isolating the MD from the typical Mediterranean lifestyle and culture (including prolonged 'social' meals and siestas), much evidence supports the health benefits of the MD that include improved longevity, reduced metabolic risk of Diabetes Mellitus, obesity, and Metabolic Syndrome, reduced risk of malignancy and cardiovascular disease, and improved cognitive function. The MD is also associated with characteristic modifications to gut microbiota, mediated through its constituent parts (primarily dietary fibres, extra virgin olive oil, and polyunsaturated fatty acids [including ω-3]). These include enhanced growth of species that produce short-chain fatty acids (butyrate), such as Clostridium leptum and Eubacterium rectale, enhanced growth of Bifidobacteria, Bacteroides, and Faecalibacterium prausnitzii species, and reduced growth of Firmicutes and Blautia species. Such changes in gut microbiota are known to be associated favourably with inflammatory and oxidative status, propensity for malignancy and overall metabolic health. A key challenge for the future is to explore the extent to which the health benefits of the MD are mediated by such changes to gut microbiota. The MD confers both health and environmental benefits. Adoption of the MD should perhaps be encouraged and facilitated more generally and not just restricted to populations from Mediterranean regions. However, there are key challenges to this approach that include limited perennial availability of the constituent parts of the MD in some non-Mediterranean regions, intolerability of a high-fibre diet for some people, and potential cultural disconnects that juxtapose some traditional (including Western) diets with the MD.

Metabolic-Associated Fatty Liver Disease and the Gut Microbiota.

As an important sequela of the burgeoning global obesity problem, metabolic-associated fatty liver disease (MAFLD) has gained increasing prominence recently. The gut-liver axis (GLA) provides a direct conduit to the liver for the gut microbiota and their metabolic by-products (including secondary bile acids, ethanol, and trimethylamine). These GLA-related factors, including the host inflammatory response and integrity of the gut mucosal wall, likely contribute to the pathogenesis of MAFLD. Accordingly, these GLA-related factors are targets for possible preventive and treatment strategies for MAFLD, and include probiotics, prebiotics, bile acids, short-chain fatty acids, fecal microbiota transplantation, carbon nanoparticles, and bacteriophages.

Metabolic-Associated Fatty Liver Disease and Insulin Resistance: A Review of Complex Interlinks.

Metabolic-associated fatty liver disease (MAFLD) has now surpassed alcohol excess as the most common cause of chronic liver disease globally, affecting one in four people. Given its prevalence, MAFLD is an important cause of cirrhosis, even though only a small proportion of patients with MAFLD ultimately progress to cirrhosis. MAFLD suffers as a clinical entity due to its insidious and often asymptomatic onset, lack of an accurate and reliable non-invasive diagnostic test, and lack of a bespoke therapy that has been designed and approved for use specifically in MAFLD. MAFLD sits at a crossroads between the gut and the periphery. The development of MAFLD (including activation of the inflammatory cascade) is influenced by gut-related factors that include the gut microbiota and intactness of the gut mucosal wall. The gut microbiota may interact directly with the liver parenchyma (through translocation via the portal vein), or indirectly through the release of metabolic metabolites that include secondary bile acids, trimethylamine, and short-chain fatty acids (such as propionate and acetate). In turn, the liver mediates the metabolic status of peripheral tissues (including insulin sensitivity) through a complex interplay of hepatokines, liver-secreted metabolites, and liver-derived micro RNAs. As such, the liver plays a key central role in influencing overall metabolic status. In this concise review, we provide an overview of the complex mechanisms whereby MAFLD influences the development of insulin resistance within the periphery, and gut-related factors impact on the development of MAFLD. We also discuss lifestyle strategies for optimising metabolic liver health.

More than skin-deep: visceral fat is strongly associated with disease activity, function and metabolic indices in psoriatic disease.

OBJECTIVE: To compare body composition between patients with psoriatic disease (PsD), including cutaneous psoriasis (PsO) and psoriatic arthritis (PsA), and controls, and to explore associations between disease activity and measures of function and metabolic derangement. METHODS: Body composition was assessed by air displacement plethysmography (ADP) and MRI-derived fat segmentation using an automated pipeline (FatSegNet). Function was assessed by Health Assessment Questionnaire (HAQ) and metabolic status by fasting lipid profile, insulin and adiponectin. Active and inactive PsO and PsA were defined by body surface area (BSA) and Psoriasis Area Severity Index (PASI) and minimal disease activity (MDA), respectively. RESULTS: Thirty patients (median disease duration 15 years; median age 52 years) and 30 BMI-matched controls were enrolled. Compared with controls, all MRI-derived body composition parameters-whole-body volume, subcutaneous adipose tissue (SAT), visceral adipose tissue (VAT), abdominal adipose tissue (AAT), VAT/AAT and VAT/SAT-were higher in the PsD group, specifically, those with active disease. Body mass, body fat, whole-body volume and whole-body VAT were correlated with higher triglycerides, cholesterol:HDL (high-density lipoprotein), insulin resistance and lower adiponectin as well as higher HAQ and lower MDA. CONCLUSIONS: In this pilot study, patients with PsD revealed excessive total adipose tissue and a greater volume of metabolically unfavourable ectopic fat, including VAT, compared with BMI-matched controls, which also correlated with HAQ, disease activity and overall dysmetabolism. We also provide the first evidence in patients with PsD for the clinical application of FatSegNet: a novel, automated and rapid deep learning pipeline for providing accurate MRI-based measurement of fat segmentation. Our findings suggest the need for a more integrated approach to the management of PsD, which considers both the metabolic and inflammatory burden of disease. More specifically, visceral fat is a surrogate marker of uncontrolled PsD and may be an important future target for both pharmacological and lifestyle interventions.

Acute iv CRH administration significantly increases serum active ghrelin in postmenopausal PCOS women compared to postmenopausal controls.

PURPOSE: In women with Polycystic Ovarian Syndrome (PCOS), an increased risk of disordered eating has been described. There is growing interest regarding a possible interconnection between psychological states and increased appetite in women with PCOS. Acute stress is characterized by increased Corticotropin Releasing Hormone (CRH) secretion. The aim was to estimate the ghrelin concentrations during CRH test. METHODS: Twenty postmenopausal women with PCOS and twenty age- and BMI- matched postmenopausal control women were recruited at Aretaieion University Hospital. In the morning (9 am) all subjects had anthropometric measurements (weight, height, waist circumference) and a fasting sample for hormonal measurements. An intravenous (iv) CRH stimulation test conducted over 1 min. Serum active ghrelin levels were measured at 0, 15, 30, 60, 90, 120 min after iv CRH administration. RESULTS: The postmenopausal PCOS group had a higher waist circumference compared to postmenopausal controls. Active ghrelin concentrations increased significantly from 0 to 15 min, to 30 min, to 60 min, to 90 min and then decreased to 120 min. However, within the postmenopausal control group there were no significant changes in serum active ghrelin levels. Serum active ghrelin concentrations were significantly greater in the postmenopausal control group at 0, 15 and 120 min compared to the postmenopausal PCOS group. At 90 min active ghrelin concentrations were significantly greater in the postmenopausal PCOS group. Delta Area Under the Curve of active ghrelin (ΔAUCghr) was significantly greater in the postmenopausal PCOS group compared to controls. CONCLUSIONS: In postmenopausal PCOS, but not in postmenopausal controls, iv CRH administration induces increased serum active ghrelin secretion, suggesting a possible anti-stress adaptive mechanism. An increase in serum active ghrelin may induce hunger as a side-effect of this presumed adaptive mechanism.

Implementation of a Digital Health Tool for Patients Awaiting Input From a Specialist Weight Management Team: Observational Study.

BACKGROUND: Digital tools are increasingly used on a population level as a weight loss strategy for people living with overweight and obesity. Evidence supports the feasibility of digital tools for the management of obesity in a community setting, but there is only emerging evidence for the feasibility of such tools in specialist weight management services. No study has assessed the uptake of digital tools among patients awaiting their first appointment with a specialist weight management service. OBJECTIVE: The objective of this study was to understand interest, acceptance, and engagement with a digital behavioral change platform to support specialist weight management. METHODS: This was an observational study registered as a service innovation. All patients on the waiting list for a first appointment in the tier 3 weight management service at University Hospitals Coventry and Warwickshire National Health Service (NHS) Trust were eligible to access the NHS-approved digital tool. Data on interest and engagement with the digital tool were collected. Routine clinical data were used to describe patient demographics. Focus groups were held to explore patients' views on the use of digital tools as part of a specialist weight management service. RESULTS: A total of 199 patients on the waiting list were informed about the available digital tool. Just over a half (n=102, 51.3%) of patients were interested in using the app, with over one-third (n=68, 34%) of all patients engaging with the app. Overall, a third of patients on the waiting list (n=63, 32%) did not respond to the invite and 34 (17%) of patients expressed no interest in the app. Emotional eating and higher BMI was associated with interest in the Gro Health app. Male gender was associated with reduced engagement with the app. There were no differences in interest in the Gro Health app according to age, ethnicity, metabolic measures of glycemia, and lipid profile. CONCLUSIONS: It is feasible to offer digital tools such as Gro Health to patients awaiting their first appointment with specialist weight management services. Future research should explore barriers and facilitators of engagement with digital tools. Additionally, there is a need to further evaluate the effectiveness of such tools in specialist weight management services.

The Role of the Vasculature in Heart Failure.

The contribution of the vasculature in the development and progression of heart failure (HF) syndromes is poorly understood and often neglected. Incorporating both arterial and venous systems, the vasculature plays a significant role in the regulation of blood flow throughout the body in meeting its metabolic requirements. A deterioration or imbalance between the cardiac and vascular interaction can precipitate acute decompensated HF in both preserved and reduced ejection fraction phenotypes. This is characterised by the increasingly recognised concept of ventricular-arterial coupling: a well-balanced relationship between ventricular and vascular stiffness, which has major implications in HF. Often, the cause of decompensation is unknown, with international guidelines mainly centred on arrhythmia, infection, acute coronary syndrome and its mechanical complications as common causes of decompensation; the vascular component is often underrecognised. A better understanding of the vascular contribution in cardiovascular failure can improve risk stratification, earlier diagnosis and facilitate earlier optimal treatment. This review focuses on the role of the vasculature by integrating the concepts of ventricular-arterial coupling, arterial stiffness and venous return in a failing heart.

Childhood, adolescent, and adulthood adiposity are associated with risk of PCOS: a Mendelian randomization study with meta-analysis.

STUDY QUESTION: What is the influence of body composition during childhood, adolescence, and adulthood, as well as metabolic parameters, on incident polycystic ovary syndrome (PCOS)? SUMMARY ANSWER: Excess body fat, even during childhood/adolescence, and metabolic parameters, suggestive of hyperinsulinaemia/insulin resistance, significantly impact the risk of PCOS in a linear fashion. WHAT IS KNOWN ALREADY: Observational and Mendelian randomization (MR) data have demonstrated an association between adulthood overweight/obesity and development of PCOS. However, the contribution of body composition in childhood/adolescence to incident PCOS is unclear, as is the influence of childhood overweight/obesity. STUDY DESIGN, SIZE, DURATION: We conducted a systematic review and meta-analysis and integrated our results with a previously published systematic review. Two blinded investigators screened abstracts published between November 2010 and May 2021. Furthermore, we incorporated summary statistics from genome-wide association study (GWAS) data in subjects of European ancestry. Adult overweight was defined as BMI ≥ 25 kg/m2 and obesity as BMI ≥ 30 kg/m2; in Asian subjects, overweight was defined as BMI ≥ 23 kg/m2 and obesity as BMI ≥ 25 kg/m2. PARTICIPANTS/MATERIALS, SETTING, METHODS: We utilized meta-analysis and MR together to allow synthesis of genetic and observational data. For the systematic review, the search revealed 71 studies, of which 63 were included in meta-analysis by calculating odds ratios (ORs) using the random-effects model. Furthermore, we conducted a two-sample MR study of GWAS data to determine the impact of childhood and adult body size (defined categorically by BMI and childhood body size proportions), abnormal body composition and metabolic parameters (higher fasting serum insulin or lower sex hormone-binding globulin (SHBG) concentration) on the odds of incident PCOS via the inverse-variance weighted method. MAIN RESULTS AND THE ROLE OF CHANCE: Significant associations were shown between body composition and PCOS incidence. From the systematic review/meta-analysis, women with overweight (OR 3.80, 2.87-5.03), obesity (OR 4.99, 3.74-6.67), and central obesity (OR 2.93, 2.08-4.12) had increased odds of PCOS. For adolescents with overweight and/or obesity, the PCOS odds were greater than for adults. From MR, for every standard deviation increase in BMI (4.8 kg/m2), the odds of PCOS increased by 2.76 (2.27-3.35). Childhood body size had an independent effect on PCOS odds after adjusting for adult body size (OR: 2.56, 1.57-4.20). Genetically determined body fat percentage (OR 3.05, 2.24-4.15), whole body fat mass (OR 2.53, 2.04-3.14), fasting serum insulin (OR 6.98, 2.02-24.13), and SHBG concentration (OR 0.74, 0.64-0.87) were all significantly associated with PCOS in a linear relation. LIMITATIONS, REASONS FOR CAUTION: The meta-analysis included studies which were cross-sectional and retrospective, limiting our ability to determine causality. MR was limited by interrogating subjects only of European ancestry and including cases classified by either self-diagnosis or diagnostic criteria. WIDER IMPLICATIONS OF THE FINDINGS: Our study demonstrates for the first time a critical role of the impact of excess childhood/adolescent adiposity on the pathophysiology of adult PCOS. Our results, driven by genetically determined childhood/adolescent body composition, higher BMI, hyperinsulinaemia, and lower SHBG, clearly favour obesity driving the metabolic, but not reproductive, PCOS phenotype. Overall, effective weight maintenance, even from the early years, is likely to reduce the risk of this reproductive endocrine disorder. STUDY FUNDING/COMPETING INTEREST(S): S.S.Z. was funded by a National Institute for Health and Care Research (NIHR) Academic Clinical Lectureship. U.A. is chair of the NIHR Steering Committee Trial-CASSANDRA-DN. No other authors declare any sources of funding or relevant conflicts of interest. The authors declare that the research was conducted in the absence of any commercial or financial relations that could be construed as a potential conflict of interest. TRIAL REGISTRATION NUMBER: N/A.

Development of an artificial intelligence system to identify hypoglycaemia via ECG in adults with type 1 diabetes: protocol for data collection under controlled and free-living conditions.

INTRODUCTION: Hypoglycaemia is a harmful potential complication in people with type 1 diabetes mellitus (T1DM) and can be exacerbated in patients receiving treatment, such as insulin therapies, by the very interventions aiming to achieve optimal blood glucose levels. Symptoms can vary greatly, including, but not limited to, trembling, palpitations, sweating, dry mouth, confusion, seizures, coma, brain damage or even death if untreated. A pilot study with healthy (euglycaemic) participants previously demonstrated that hypoglycaemia can be detected non-invasively with artificial intelligence (AI) using physiological signals obtained from wearable sensors. This protocol provides a methodological description of an observational study for obtaining physiological data from people with T1DM. The aim of this work is to further improve the previously developed AI model and validate its performance for glycaemic event detection in people with T1DM. Such a model could be suitable for integrating into a continuous, non-invasive, glucose monitoring system, contributing towards improving surveillance and management of blood glucose for people with diabetes. METHODS AND ANALYSIS: This observational study aims to recruit 30 patients with T1DM from a diabetes outpatient clinic at the University Hospital Coventry and Warwickshire for a two-phase study. The first phase involves attending an inpatient protocol for up to 36 hours in a calorimetry room under controlled conditions, followed by a phase of free-living, for up to 3 days, in which participants will go about their normal daily activities unrestricted. Throughout the study, the participants will wear wearable sensors to measure and record physiological signals (eg, ECG and continuous glucose monitor). Data collected will be used to develop and validate an AI model using state-of-the-art deep learning methods. ETHICS AND DISSEMINATION: This study has received ethical approval from National Research Ethics Service (ref: 17/NW/0277). The findings will be disseminated via peer-reviewed journals and presented at scientific conferences. TRIAL REGISTRATION NUMBER: NCT05461144.

Designer GLP1 poly-agonist peptides in the management of diabesity.

INTRODUCTION: To date, the 21st Century has witnessed key developments in the management of diabesity (a conflation of obesity and Type 2 Diabetes Mellitus [T2D]), including Glucagon Like Peptide 1 (GLP1) receptor agonist therapies, and recently the 'designer' GLP1 Poly-agonist Peptides (GLP1PPs). AREAS COVERED: A PubMed search of published data on the GLP1PP class of therapies was conducted. The gut-brain axis forms complex multi-directional interlinks that include autonomic nervous signaling, components of the gut microbiota (including metabolic by-products and gram-negative cell wall components [e.g. endotoxinaemia]), and incretin hormones that are secreted from the gut in response to the ingestion of nutrients. The development of dual-incretin agonist therapies includes combinations of the GLP1 peptide with Glucose-dependent Insulinotropic Polypeptide (GIP), Glucagon (Gcg), Cholecystokinin (CCK), Peptide YY (PYY), and Glucagon-Like Peptide 2 (GLP2). Triple incretin agonist therapies are also under development. EXPERT OPINION: At the dawn of a new era in the therapeutic management of diabesity, the designer GLP1PP class holds great promise, with each novel combination building on a preexisting palimpsest of clinical data and insights. Future innovations of the GLP1PP class will likely enable medically induced weight loss and glycemic control in diabesity to rival or even out-perform those resulting from bariatric surgery.

Obesity Stigma: Causes, Consequences, and Potential Solutions.

PURPOSE OF REVIEW: This review aims to examine (i) the aetiology of obesity; (ii) how and why a perception of personal responsibility for obesity so dominantly frames this condition and how this mindset leads to stigma; (iii) the consequences of obesity stigma for people living with obesity, and for the public support for interventions to prevent and manage this condition; and (iv) potential strategies to diminish our focus on personal responsibility for the development of obesity, to enable a reduction of obesity stigma, and to move towards effective interventions to prevent and manage obesity within the population. RECENT FINDINGS: We summarise literature which shows that obesity stems from a complex interplay of genetic and environment factors most of which are outside an individual's control. Despite this, evidence of obesity stigmatisation remains abundant throughout areas of media, entertainment, social media and the internet, advertising, news outlets, and the political and public health landscape. This has damaging consequences including psychological, physical, and socioeconomic harm. Obesity stigma does not prevent obesity. A combined, concerted, and sustained effort from multiple stakeholders and key decision-makers within society is required to dispel myths around personal responsibility for body weight, and to foster more empathy for people living in larger bodies. This also sets the scene for more effective policies and interventions, targeting the social and environmental drivers of health, to ultimately improve population health.

Preconception Vitamin D Level and In Vitro Fertilization: Pregnancy Outcome.

OBJECTIVE: Vitamin D deficiency impairs female fertility and the success of in vitro fertilization (IVF). The recommended serum 25-hydroxyvitamin D (25(OH)D) level in IVF-conceived pregnancies is still debated. We aimed to explore the relationship of the preconception serum 25(OH)D level with pregnancy outcome following IVF treatment. We also explored the utility of the currently recommended serum 25(OH)D cutoff of ≥50 nmol/L for women undergoing IVF therapy. METHODS: Retrospective cohort of women who had undergone IVF therapy. Of the women who started IVF therapy (n = 354), 218 completed the study. They were divided into 2 groups: (1) women who achieved a successful pregnancy (pregnant group, n = 160) and (2) those who did not achieve a successful pregnancy (nonpregnant group, n = 58). Preconception serum samples were analyzed for reproductive hormones, fasting glucose, insulin, and 25(OH)D levels. RESULTS: Overall, the median (interquartile range) age, body mass index, and hemoglobin A1c level were 32 (6) years, 25.7 (7.4) kg/m2, and 5.2% (0.6%), respectively. The 25(OH)D level was significantly higher at preconception in the pregnant group (56.4 [21.4] vs 47.9 [29.16] for nonpregnant, P = .001). The preconception 25(OH)D level was a significant predictor of IVF outcome (B = 0.04; 95% CI, 1.01-1.06; P = .001), with greater IVF success associated with a serum 25(OH)D level of ≥50 nmol/L (odds ratio, 0.46; P = .01). CONCLUSION: Preconception 25(OH)D sufficiency (≥50 nmol/L) is associated with successful pregnancy outcome following IVF therapy.

The DAPA-DIET study: Metabolic response to Dapagliflozin combined with dietary carbohydrate restriction in patients with Type 2 Diabetes Mellitus and Obesity-A longitudinal cohort study.

OBJECTIVE: The cardio-renal benefits of sodium glucose-like transporter 2 inhibitor (SGLT2i) therapies have been demonstrated in patients with and without type 2 diabetes. However, no studies have explored the long-term metabolic effects of SGLT2i, combined with dietary carbohydrate restriction. Our primary objective was to describe long-term changes in weight, energy expenditure, appetite and body composition after 12 months of Dapagliflozin therapy, with carbohydrate restriction, in people with type 2 diabetes and obesity. Our secondary objective was to assess changes in adiponectin and leptin. METHOD: This was a 12-month cohort study in a secondary care setting. Participants (n = 18) with type 2 diabetes (T2D) and class 3 obesity underwent baseline indirect calorimetry for determination of 24-h energy expenditure, body composition, fasting serum leptin and adiponectin levels, and appetitive assessments. Following initiation of Dapagliflozin (and dietary carbohydrate restriction), measurements were repeated at monthly intervals up to 12 months. RESULTS: Mean starting weight of participants was 129.4 kg (SD 25.9), mean BMI 46.1 kg/m2 (SD 8.3) and mean HbA1c 53.9 mmol/mol (14.1). Seventeen participants completed the study; after 12 months of Dapagliflozin and dietary carbohydrate restriction, mean weight loss was 8.1 kg (SD 11.3 kg; p = .009). This was mediated by reduced fat mass (mean loss, 9.9 kg; SD 10.4 kg; p = .002) associated with reduced serum leptin at 12 months (mean reduction 11,254 pg/ml; SD 16,075; p = .011). There were no significant changes in self-reported appetite, 24-h energy expenditure or serum adiponectin during follow-up. CONCLUSION: In this study, combined Dapagliflozin therapy and carbohydrate restriction in patients with T2D and obesity resulted in a significant reduction of body weight and fat mass at 12 months without any discernible changes in energy expenditure or appetite. These results offer a scientific and clinical rationale to conduct an exploratory trial investigating the effects of a low carbohydrate diet combined with SGLT2 inhibitors in patients with T2D.

Relationship between Maternal Serum Thyroid-Stimulating Hormone and in vitro Fertilisation-Conceived Pregnancy Outcomes.

Background: Thyroid dysfunction impairs female fertility and pregnancy outcome. Optimal preconception and gestational TSH level is still debatable in IVF-conceived pregnancies. Aims: To explore the relationships of IVF success and pregnancy outcomes with maternal serum levels of TSH (at both preconception and 12-week IVF-conceived pregnancy). Also, to confirm or refute the recommended TSH level ≤2.5µIU/mL. Study Setting and Design: Retrospective cohort. Material and Methods: 158 IVF-conceived pregnant women and 117 age-matched controls non-pregnant (≤39years, BMI 18.5-38kg/m2) were recruited. Preconception and 12-week IVF-conceived pregnancy serum samples were analysed for reproductive hormones, fasting glucose, insulin and TSH levels. Data of pregnant women at 28 weeks for GDM screening (75-gram OGTT) and up until delivery were included. Statistical Analysis: Binary logistic regression used to predict association between preconception TSH levels and IVF success, and pregnancy outcomes. Association of delta change of hormones was determined with linear regression. Significance level P≤0.05 with 95% confidence interval (CI). Results: Overall, median (IQR) age was 32(6)years, BMI 25.4(6.9)kg/m2, HbA1c 5.2(0.52)% and TSH 1.82(1.4)µIU/mL. There was no significant association between preconception TSH level and IVF success rate. During the first trimester of IVF-conceived pregnancy, delta change in TSH level was associated with that of progesterone (P=0.03). 12-week gestation TSH level did not predict adverse pregnancy outcomes (i.e. onset of GDM, delivery type and premature delivery); but a higher TSH level predicted earlier delivery in weeks. There was a higher risk of delivery by caesarean section when TSH>2.5µIU/mL. Conclusion: Variation of maternal TSH within normal range (0.4-4.0µIU/mL) at preconception and 12-week gestation has no predictive effect on IVF success and pregnancy outcomes in IVF-pregnancy. Our data provide no support for a recommended preconception TSH level ≤2.5µIU/mL in IVF-conceived pregnancy, but rather promote a preconception TSH level within normal range.

Implications of Resveratrol in Obesity and Insulin Resistance: A State-of-the-Art Review.

Background: Resveratrol is a polyphenol chemical that naturally occurs in many plant-based dietary products, most notably, red wine. Discovered in 1939, widespread interest in the potential health benefits of resveratrol emerged in the 1970s in response to epidemiological data on the cardioprotective effects of wine. Objective: To explore the background of resveratrol (including its origins, stability, and metabolism), the metabolic effects of resveratrol and its mechanisms of action, and a potential future role of dietary resveratrol in the lifestyle management of obesity. Data sources: We performed a narrative review, based on relevant articles written in English from a Pubmed search, using the following search terms: "resveratrol", "obesity", "Diabetes Mellitus", and "insulin sensitivity". Results: Following its ingestion, resveratrol undergoes extensive metabolism. This includes conjugation (with sulfate and glucuronate) within enterocytes, hydrolyzation and reduction within the gut through the action of the microbiota (with the formation of metabolites such as dihydroresveratrol), and enterohepatic circulation via the bile. Ex vivo studies on adipose tissue reveal that resveratrol inhibits adipogenesis and prevents the accumulation of triglycerides through effects on the expression of Peroxisome Proliferator-activated Receptor γ (PPARγ) and sirtuin 1, respectively. Furthermore, resveratrol induces anti-inflammatory effects, supported by data from animal-based studies. Limited data from human-based studies reveal that resveratrol improves insulin sensitivity and fasting glucose levels in patients with Type 2 Diabetes Mellitus and may improve inflammatory status in human obesity. Although numerous mechanisms may underlie the metabolic benefits of resveratrol, evidence supports a role in its interaction with the gut microbiota and modulation of protein targets, including sirtuins and proteins related to nitric oxide, insulin, and nuclear hormone receptors (such as PPARγ). Conclusions: Despite much interest, there remain important unanswered questions regarding its optimal dosage (and how this may differ between and within individuals), and possible benefits within the general population, including the potential for weight-loss and improved metabolic function. Future studies should properly address these important questions before we can advocate the widespread adoption of dietary resveratrol supplementation.