The metabolic consequences of 'yo-yo' dieting are markedly influenced by genetic diversity.

BACKGROUND: Weight loss can improve the metabolic complications of obesity. However, it is unclear whether insulin resistance persists despite weight loss and whether any protective benefits are preserved following weight regain (weight cycling). The impact of genetic background on weight cycling is undocumented. We aimed to investigate the effects of weight loss and weight cycling on metabolic outcomes and sought to clarify the role of genetics in this relationship. METHOD: Both C57BL/6 J and genetically heterogeneous Diversity Outbred Australia (DOz) mice were alternately fed high fat Western-style diet (WD) and a chow diet at 8-week intervals. Metabolic measures including body composition, glucose tolerance, pancreatic beta cell activity, liver lipid levels and adipose tissue insulin sensitivity were determined. RESULTS: After diet switch from WD (8-week) to chow (8-week), C57BL/6 J mice displayed a rapid normalisation of body weight, adiposity, hyperinsulinemia, liver lipid levels and glucose uptake into adipose tissue comparable to chow-fed controls. In response to the same dietary intervention, genetically diverse DOz mice conversely maintained significantly higher fat mass and insulin levels compared to chow-fed controls and exhibited much more profound interindividual variability than C57BL/6 J mice. Weight cycled (WC) animals were re-exposed to WD (8-week) and compared to age-matched controls fed 8-week WD for the first time (LOb). In C57BL/6 J but not DOz mice, WC animals had significantly higher blood insulin levels than LOb controls. All WC animals exhibited significantly greater beta cell activity than LOb controls despite similar fat mass, glucose tolerance, liver lipid levels and insulin-stimulated glucose uptake in adipose tissue. CONCLUSION: Following weight loss, metabolic outcomes return to baseline in C57BL/6 J mice with obesity. However, genetic diversity significantly impacts this response. A period of weight loss does not provide lasting benefits after weight regain, and weight cycling is detrimental and associated with hyperinsulinemia and elevated basal insulin secretion.

Reducing cardiometabolic risk with semaglutide in type 1 diabetes (RESET1): Study protocol of a phase 2 double-blinded randomised placebo-controlled trial.

BACKGROUND: Premature cardiovascular disease is the leading cause of death in people living with type 1 diabetes. Therapies are urgently needed to address cardiovascular risk in this group. Semaglutide, a long-acting glucagon-like peptide-1 receptor agonist, has been shown to reduce cardiovascular events and improve weight and glycaemia in type 2 diabetes. Semaglutide may offer cardioprotective and metabolic benefits in type 1 diabetes. METHODS: We will study 60 adults aged 25-70 years with type 1 diabetes of duration at least 2 years, body mass index ≥25 kg/m2, HbA1c ≥7% and at least one cardiovascular risk factor (microalbuminuria, hypertension or anti-hypertensive treatment, hyperlipidemia or lipid lowering therapy, current smoking). Participants will receive semaglutide up to 1.0 mg weekly or matched placebo for 26 weeks. The primary outcome is carotid femoral pulse wave velocity, a measure of arterial stiffness, as a surrogate marker of cardiovascular risk. Potential mechanisms for metabolic changes will be explored including change in insulin sensitivity determined by hyperinsulinaemic-euglycaemic clamp; and incretin and pancreatic hormone action measured during mixed meal tolerance test. CONCLUSION: The REducing cardiometabolic risk with SEmaglutide in Type 1 diabetes study will investigate whether semaglutide, a long acting glucagon-like peptide receptor agonist, can improve markers of cardiometabolic health in T1D. Underlying mechanisms predicting response, including insulin resistance and incretin hormone status, will also be explored.

Individualised prescription of medications for treatment of obesity in adults.

Obesity continues to increase in prevalence globally, driven by changes in environmental factors which have accelerated the development of obesity in individuals with an underlying predisposition to weight gain. The adverse health effects and increased risk for chronic disease associated with obesity are ameliorated by weight loss, with greater benefits from larger amounts of weight reduction. Obesity is a heterogeneous condition, with the drivers, phenotype and complications differing substantially between individuals. This raises the question of whether treatments for obesity, specifically pharmacotherapy, can be targeted based on individual characteristics. This review examines the rationale and the clinical data evaluating this strategy in adults. Individualised prescribing of obesity medication has been successful in rare cases of monogenic obesity where medications have been developed to target dysfunctions in leptin/melanocortin signalling pathways but has been unsuccessful in polygenic obesity due to a lack of understanding of how the gene variants associated with body mass index affect phenotype. At present, the only factor consistently associated with longer-term efficacy of obesity pharmacotherapy is early weight loss outcome, which cannot inform choice of therapy at the time of medication initiation. The concept of matching a therapy for obesity to the characteristics of the individual is appealing but as yet unproven in randomised clinical trials. With increasing technology allowing deeper phenotyping of individuals, increased sophistication in the analysis of big data and the emergence of new treatments, it is possible that precision medicine for obesity will eventuate. For now, a personalised approach that takes into account the person's context, preferences, comorbidities and contraindications is recommended.

Maternal and neonatal outcomes of women with gestational diabetes and without specific medical conditions: an Australian population-based study comparing induction of labor with expectant management.

BACKGROUND/AIMS: To evaluate maternal birth and neonatal outcomes among women with gestational diabetes mellitus (GDM), but without specific medical conditions and eligible for vaginal birth who underwent induction of labour (IOL) at term compared with those who were expectantly managed. MATERIALS AND METHODS: Population-based cohort study of women with GDM, but without medical conditions, who had a singleton, cephalic birth at 38-41 completed weeks gestation, in New South Wales, Australia between January 2010 and December 2016. Women who underwent IOL at 38, 39, 40 weeks gestation (38-, 39-, 40-induction groups) were compared with those who were managed expectantly and gave birth at and/or beyond the respective gestational age group (38-, 39-, 40-expectant groups). Multivariable logistic regression analysis was used to assess the association between IOL and adverse maternal birth and neonatal outcomes taking into account potential confounding by maternal age, country of birth, smoking, residential location, residential area of socioeconomic disadvantage and birth year. RESULTS: Of 676 762 women who gave birth during the study period, 66 606 (10%) had GDM; of these, 34799 met the inclusion criteria. Compared with expectant management, those in 38- (adjusted odds ratio (aOR) 1.11; 95% CI, 1.04-1.18), 39- (aOR 1.21; 95% CI, 1.14-1.28) and 40- (aOR 1.50; 95% CI, 1.40-1.60) induction groups had increased risk of caesarean section. Women in the 38-induction group also had an increased risk of composite neonatal morbidity (aOR 1.10; 95% CI, 1.01-1.21), which was not observed at 39- and 40-induction groups. We found no difference between groups in perinatal death or neonatal intensive care unit admission for births at any gestational age. CONCLUSION: In women with GDM but without specific medical conditions and eligible for vaginal birth, IOL at 38, 39, 40 weeks gestation is associated with an increased risk of caesarean section.

Small-protein Enrichment Assay Enables the Rapid, Unbiased Analysis of Over 100 Low Abundance Factors from Human Plasma.

Unbiased and sensitive quantification of low abundance small proteins in human plasma (e.g. hormones, immune factors, metabolic regulators) remains an unmet need. These small protein factors are typically analyzed individually and using antibodies that can lack specificity. Mass spectrometry (MS)-based proteomics has the potential to address these problems, however the analysis of plasma by MS is plagued by the extremely large dynamic range of this body fluid, with protein abundances spanning at least 13 orders of magnitude. Here we describe an enrichment assay (SPEA), that greatly simplifies the plasma dynamic range problem by enriching small-proteins of 2-10 kDa, enabling the rapid, specific and sensitive quantification of >100 small-protein factors in a single untargeted LC-MS/MS acquisition. Applying this method to perform deep-proteome profiling of human plasma we identify C5ORF46 as a previously uncharacterized human plasma protein. We further demonstrate the reproducibility of our workflow for low abundance protein analysis using a stable-isotope labeled protein standard of insulin spiked into human plasma. SPEA provides the ability to study numerous important hormones in a single rapid assay, which we applied to study the intermittent fasting response and observed several unexpected changes including decreased plasma abundance of the iron homeostasis regulator hepcidin.

Muscle and adipose tissue insulin resistance: malady without mechanism?

Insulin resistance is a major risk factor for numerous diseases, including type 2 diabetes and cardiovascular disease. These disorders have dramatically increased in incidence with modern life, suggesting that excess nutrients and obesity are major causes of "common" insulin resistance. Despite considerable effort, the mechanisms that contribute to common insulin resistance are not resolved. There is universal agreement that extracellular perturbations, such as nutrient excess, hyperinsulinemia, glucocorticoids, or inflammation, trigger intracellular stress in key metabolic target tissues, such as muscle and adipose tissue, and this impairs the ability of insulin to initiate its normal metabolic actions in these cells. Here, we present evidence that the impairment in insulin action is independent of proximal elements of the insulin signaling pathway and is likely specific to the glucoregulatory branch of insulin signaling. We propose that many intracellular stress pathways act in concert to increase mitochondrial reactive oxygen species to trigger insulin resistance. We speculate that this may be a physiological pathway to conserve glucose during specific states, such as fasting, and that, in the presence of chronic nutrient excess, this pathway ultimately leads to disease. This review highlights key points in this pathway that require further research effort.

Proteomic Analysis of Human Plasma during Intermittent Fasting.

Intermittent fasting (IF) increases lifespan and decreases metabolic disease phenotypes and cancer risk in model organisms, but the health benefits of IF in humans are less clear. Human plasma derived from clinical trials is one of the most difficult sample sets to analyze using mass spectrometry-based proteomics due to the extensive sample preparation required and the need to process many samples to achieve statistical significance. Here, we describe an optimized and accessible device (Spin96) to accommodate up to 96 StageTips, a widely used sample preparation medium enabling efficient and consistent processing of samples prior to LC-MS/MS. We have applied this device to the analysis of human plasma from a clinical trial of IF. In this longitudinal study employing 8-weeks IF, we identified significant abundance differences induced by the IF intervention, including increased apolipoprotein A4 (APOA4) and decreased apolipoprotein C2 (APOC2) and C3 (APOC3). These changes correlated with a significant decrease in plasma triglycerides after the IF intervention. Given that these proteins have a role in regulating apolipoprotein particle metabolism, we propose that IF had a positive effect on lipid metabolism through modulation of HDL particle size and function. In addition, we applied a novel human protein variant database to detect common protein variants across the participants. We show that consistent detection of clinically relevant peptides derived from both alleles of many proteins is possible, including some that are associated with human metabolic phenotypes. Together, these findings illustrate the power of accessible workflows for proteomics analysis of clinical samples to yield significant biological insight.

Utility of the Hospital Admission Risk Programme diabetes risk calculator in identifying patients with type 2 diabetes at risk of unplanned hospital presentations.

BACKGROUND: Prevention of hospitalisation is an important aspect of type 2 diabetes (T2D) management. AIMS: We retrospectively determined the utility of the Hospital Admission Risk Programme (HARP) diabetes risk calculator (HARP tool) in identifying patients with T2D more likely to have unplanned hospital presentations. METHODS: The HARP tool includes a clinical assessment score (Part A) and a psychosocial and self-management impact score (Part B), and categorises patients into low, medium, high or urgent risk of acute hospitalisation. It was completed for T2D patients attending Royal North Shore Hospital, Sydney, in 2013. RESULTS: Within the cohort of 278 patients (age 65.3 ± 10.5 years; 62.9% male; diabetes duration 10.7 ± 6.6 years), 67.3% were classified as low risk, 32.7% as medium risk and none as high or urgent risk. Following adjustment for confounders, a medium HARP score was associated with a 3.1-fold increased risk of unplanned hospital presentations in the subsequent 12 months (95% confidence interval: 1.35-7.31; P = 0.008). Part A scores were significantly higher for patients that presented to hospital compared to those that did not (14.2 ± 6.8 vs 11.4 ± 5.5; P = 0.034), whereas there was no difference in Part B scores (P = 0.860). CONCLUSIONS: In patients with low and medium HARP scores, clinical features were more predictive of hospital presentations than certain psychosocial or self-management factors in the present cohort. Further studies are required to characterise unplanned hospitalisation in patients with higher HARP scores, or whether additional psychosocial assessments could improve the tool's predictability.

Identification of Patients With Diabetes Who Benefit Most From a Health Coaching Program in Chronic Disease Management, Sydney, Australia, 2013.

INTRODUCTION: Chronic disease management programs (CDMPs) that include health coaching can facilitate and coordinate diabetes management. The aim of this study was to assess changes in patients' general knowledge of diabetes, self-reported health status, diabetes distress, body mass index (BMI), and glycemic control after enrollment in a face-to-face CDMP group health coaching session (with telephone follow-up) compared with participation in telephone-only health coaching, during a 12-month period. METHODS: Patients with diabetes were enrolled in a health coaching program at Royal North Shore Hospital, Sydney, Australia, in 2013. Questionnaires were administered at baseline and at 3, 6, and 12 months, and the results were compared with baseline. Glycemic control, measured with glycated hemoglobin A1c (HbA1c) and BMI, were measured at baseline and 12 months. RESULTS: Overall, 238 patients attended a face-to-face CDMP session with telephone follow-up (n = 178) or participated in telephone-only health coaching (n = 60). We found no change in BMI in either group; however, HbA1c levels in patients with baseline above the current recommended target (>7%) decreased significantly from 8.5% (standard deviation [SD], 1.0%) to 7.9% (SD, 1.0%) (P = .03). Patients with the lowest self-reported health status at baseline improved from 4.4 (SD, 0.5) to 3.7 (SD, 0.9) (P = .001). Diabetes knowledge improved in all patients (24.4 [SD, 2.4] to 25.2 [SD, 2.4]; P < .001), and diabetes distress decreased among those with the highest levels of distress at baseline (3.0 [SD, 0.4] vs 3.8 [SD, 0.6]; P = .003). CONCLUSION: Diabetes health coaching programs can improve glycemic control and reduce diabetes distress in patients with high levels of these at baseline.

Impact of obesity and epicardial fat on early left atrial dysfunction assessed by cardiac MRI strain analysis.

BACKGROUND: Diastolic dysfunction is a major cause of morbidity in obese individuals. We aimed to assess the ability of magnetic resonance imaging (MRI) derived left atrial (LA) strain to detect early diastolic dysfunction in individuals with obesity and type 2 diabetes, and to explore the association between cardiac adipose tissue and LA function. METHODS: Twenty patients with obesity and T2D (55 ± 8 years) and nineteen healthy controls (48 ± 13 years) were imaged using cine steady state free precession and 2-point Dixon cardiovascular magnetic resonance. LA function was quantified using a feature tracking technique with definition of phasic longitudinal strain and strain rates, as well as radial motion fraction and radial velocities. RESULTS: Systolic left ventricular size and function were similar between the obesity and type 2 diabetes and control groups by MRI. All patients except four had normal diastolic assessment by echocardiography. In contrast, measures of LA function using magnetic resonance feature tracking were uniformly altered in the obesity and type 2 diabetes group only. Although there was no significant difference in intra-myocardial fat fraction, Dixon 3D epicardial fat volume(EFV) was significantly elevated in the obesity and type 2 diabetes versus control group (135 ± 31 vs. 90 ± 30 mL/m2, p < 0.001). There were significant correlations between LA functional indices and both BMI and EFV (p ≤ 0.007). CONCLUSIONS: LA MRI-strain may be a sensitive tool for the detection of early diastolic dysfunction in individuals with obesity and type 2 diabetes and correlated with BMI and epicardial fat supporting a possible association between adiposity and LA strain. Trials Registration Australian New Zealand Clinical Trials Registry No. ACTRN12613001069741.

Subcutaneous fat transplantation alleviates diet-induced glucose intolerance and inflammation in mice.

AIMS/HYPOTHESIS: Adipose tissue (AT) distribution is a major determinant of mortality and morbidity in obesity. In mice, intra-abdominal transplantation of subcutaneous AT (SAT) protects against glucose intolerance and insulin resistance (IR), but the underlying mechanisms are not well understood. METHODS: We investigated changes in adipokines, tissue-specific glucose uptake, gene expression and systemic inflammation in male C57BL6/J mice implanted intra-abdominally with either inguinal SAT or epididymal visceral AT (VAT) and fed a high-fat diet (HFD) for up to 17 weeks. RESULTS: Glucose tolerance was improved in mice receiving SAT after 6 weeks, and this was not attributable to differences in adiposity, tissue-specific glucose uptake, or plasma leptin or adiponectin concentrations. Instead, SAT transplantation prevented HFD-induced hepatic triacylglycerol accumulation and normalised the expression of hepatic gluconeogenic enzymes. Grafted fat displayed a significant increase in glucose uptake and unexpectedly, an induction of skeletal muscle-specific gene expression. Mice receiving subcutaneous fat also displayed a marked reduction in the plasma concentrations of several proinflammatory cytokines (TNF-α, IL-17, IL-12p70, monocyte chemoattractant protein-1 [MCP-1] and macrophage inflammatory protein-1ß [ΜIP-1ß]), compared with sham-operated mice. Plasma IL-17 and MIP-1ß concentrations were reduced from as early as 4 weeks after transplantation, and differences in plasma TNF-α and IL-17 concentrations predicted glucose tolerance and insulinaemia in the entire cohort of mice (n = 40). In contrast, mice receiving visceral fat transplants were glucose intolerant, with increased hepatic triacylglycerol content and elevated plasma IL-6 concentrations. CONCLUSIONS/INTERPRETATION: Intra-abdominal transplantation of subcutaneous fat reverses HFD-induced glucose intolerance, hepatic triacylglycerol accumulation and systemic inflammation in mice.

Intensive Lifestyle Intervention for Remission of Early Type 2 Diabetes in Primary Care in Australia: DiRECT-Aus.

OBJECTIVE: We aimed to assess whether remission of type 2 diabetes (T2D) could be achieved with a low-energy total diet replacement (TDR) in an Australian primary care setting. RESEARCH DESIGN AND METHODS: Individuals aged 20-65 years with T2D duration up to 6 years, BMI >27.0 kg/m2, and not treated with insulin were prescribed a 13-week low-energy TDR (Optifast; Nestlé Health Science) followed by 8-week structured food reintroduction and 31-week supported weight maintenance. The primary outcome was T2D remission at 12 months. RESULTS: A total of 155 participants comprised the intention-to-treat population. At 12 months, T2D remission was achieved in 86 (56%) participants, with a mean adjusted weight loss of 8.1% (95% CI 7.2-9.1). Two serious adverse events requiring hospitalization related to the study intervention were reported. CONCLUSIONS: At 12 months T2D remission was achieved for one in two Australian adults in a primary care setting.

Applications of SGLT2 inhibitors beyond glycaemic control.

Sodium-glucose cotransporter 2 (SGLT2) inhibitors were initially developed for their glucose-lowering effects and have shown a modest glycaemic benefit in people with type 2 diabetes mellitus (T2DM). In the past decade, a series of large, robust clinical trials of these therapies have demonstrated striking beneficial effects for various care goals, transforming the chronic disease therapeutic landscape. Cardiovascular safety studies in people with T2DM demonstrated that SGLT2 inhibitors reduce cardiovascular death and hospitalization for heart failure. Subsequent trials in participants with heart failure with reduced or preserved left ventricular ejection fraction demonstrated that SGLT2 inhibitors have beneficial effects on heart failure outcomes. In dedicated kidney outcome studies, SGLT2 inhibitors reduced the incidence of kidney failure among participants with or without diabetes. Post hoc analyses have suggested a range of other benefits of these drugs in conditions as diverse as metabolic dysfunction-associated steatotic liver disease, kidney stone prevention and anaemia. SGLT2 inhibitors have a generally favourable adverse effect profile, although patient selection and medication counselling remain important. Concerted efforts are needed to better integrate these agents into routine care and support long-term medication adherence to close the gap between clinical trial outcomes and those achieved in the real world.

Metabolic effects of lipectomy and of adipose tissue transplantation.

OBJECTIVE: The goal of this study was to review the metabolic effects of fat transplantation. METHODS: Fat (adipose tissue [AT]) transplantation has been performed extensively for many years in the cosmetic reconstruction industry. However, not all fats are equal. White, brown, and beige AT differ in energy storage and use. Brown and beige AT consume glucose and lipids for thermogenesis and, theoretically, may provide greater metabolic benefit in transplantation. Here, the authors review the metabolic effects of AT transplantation. RESULTS: Removal of subcutaneous human AT does not have beneficial metabolic effects. Most studies find no benefit from visceral AT transplantation and some studies report harmful effects. In contrast, transplantation of inguinal or subcutaneous AT in mice has positive effects. Brown AT transplant studies have variable results depending on the model but most show benefit. CONCLUSIONS: Many technical improvements have optimized fat grafting and transplantation in cosmetic surgery. Transplantation of subcutaneous AT has the potential for significant metabolic benefits, although there are few studies in humans or using human AT. Brown AT transplantation is beneficial but not readily feasible in humans thus ex vivo "beiging" may be a useful strategy. AT transplantation may provide clinical benefits in metabolic disorders, especially in the setting of lipodystrophy.

Motivations for participation in weight loss clinical trials.

Males are under-represented in weight loss clinical trials, usually comprising fewer than one-quarter of participants. Our study aimed to investigate people's motivations for participating in weight loss trials and determine any relationship with gender. Eighty individuals from an existing registry for weight loss trials were contacted, of whom 24 (9 males, 15 females) agreed to participate in a 20-min semi-structured interview around their expectations and motivations for volunteering. Interviews were audio-recorded and transcribed in Zoom. A transcript of each interview was uploaded into NVivo for preliminary thematic analysis. Improved health was a common motivation for pursuing weight loss in all subjects regardless of gender. Male recruitment to weight loss trials was often influenced by advice from a healthcare professional to lose weight for the prevention of obesity-related comorbidities, whereas family and aesthetic expectations (e.g., clothes and fashion) were key elements of female participation. Identification of gender differences in motivations for volunteering in weight loss trials will help improve tailoring of recruitment strategies and interventions to enhance male participation in the future.

Obesity, lifestyle behaviours and psychological effects of the COVID-19 lockdown: A survey of patients attending a tertiary weight loss clinic.

Lockdown measures due to coronavirus-19 disease (COVID-19) have impacted lifestyle factors. This study aimed to explore whether health and lifestyle behaviours changed during the 2020 COVID-19 lockdown among patients with obesity. A specifically designed online survey and the Depression Anxiety Stress Scale (DASS-21) were administered to patients scheduled to attend a tertiary weight management service between 6 June-12 August 2020. A total of 210 participants completed the survey; mean age (SD) was 52.1 (12.5) years, 69% female and 67% Caucasian. Only 1.4% had tested positive to COVID-19. There was a statistically significant increase in weight pre- and post-COVID-19 lockdown, with no sex differences. Most (61.3%) gained weight, 30.4% lost weight and 8.3% maintained. The majority changed their overall purchasing (88.4%) and eating behaviours (91.6%). Two-thirds (64%) reported they did some form of exercise during the lockdown. Of those, exercise declined in 56.8% and increased in 18%. DASS-21 scores were positively correlated to worry about COVID-19, eating fewer core foods and eating more convenient/treat foods and negatively correlated with exercise. The results provide insights into how and why behaviour change occurs during stressful periods like the COVID-19 pandemic. Although there was variability in individual weight trajectories, on average people with obesity gained weight and changed lifestyle behaviours during the COVID-19 lockdown period. Strategies and support for people with obesity are required at these times.

Understanding the confluence of injury and obesity in a Grade 2 obesity and above population.

OBJECTIVE: Obesity and injury are major inter-related public health challenges. The objective of this study was to explore the perceptions of injury in people with severe obesity. METHODS: A cross-sectional design was employed to capture injury perception and lifestyle habits via questionnaires. Weight (kg) and height (m) were measured by clinicians for patients attending a weight loss group program. Univariate, chi-square, ANOVA and ordinal regression analyses were undertaken. RESULTS: There were 292 participants (67.1% female), mean age 49.3 years and Body Mass Index 47.2 kg/m2 (range 30.7-91.9 kg/m2). Concern about having an injury was found in 83%, and 74.2% thought that weight would increase the likelihood of injury. A greater concern of being injured at baseline was associated with less weight loss at eight weeks (F=3.567; p=0.03). Depression, anxiety and sleepiness score were higher in those who reported greater 'Concern about having an injury'. CONCLUSIONS: People with obesity fear injury and falling, which limits their willingness to exercise. Anxiety symptoms appear to exacerbate this connection. IMPLICATIONS FOR PUBLIC HEALTH: In individuals with obesity, anxiety, sleepiness and depression are associated with a fear of being injured. Addressing fear and reducing anxiety may decrease barriers to participating in physical activity.

Challenging Clinical Perspectives in Type 2 Diabetes with Tirzepatide, a First-in-Class Twincretin.

Tirzepatide is a first-in-class GIP/GLP-1 receptor agonist ('twincretin')-a single molecule that acts as an agonist at both glucagon-like peptide 1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) receptors. In the SURPASS clinical trial program in type 2 diabetes mellitus (T2D), tirzepatide was associated with unprecedented reductions in HbA1c, clinically significant weight loss and other metabolic benefits, combined with low rates of hypoglycaemia across a wide range of patient characteristics. The safety and adverse event rate for tirzepatide appears comparable to that of GLP-1 receptor agonists. Although results from dedicated cardiovascular (CV) and kidney trials are currently not available, information to date suggests that tirzepatide may have CV and kidney benefits in people with T2D. Tirzepatide has been approved for the treatment of T2D in the USA, United Arab Emirates, European Union, Japan and Australia. Here, we review how tirzepatide will fit into the T2D treatment continuum. We also consider future directions with tirzepatide in T2D, including its potential for targeting cardio-renal-metabolic disease in T2D, and discuss how tirzepatide-and other co-agonists in development-may challenge current approaches for management of T2D.

Obesity in South and Southeast Asia-A new consensus on care and management.

Obesity is a chronic disease in which the abnormal or excessive accumulation of body fat leads to impaired health and increased risk of mortality and chronic health complications. Prevalence of obesity is rising rapidly in South and Southeast Asia, with potentially serious consequences for local economies, healthcare systems, and quality of life. Our group of obesity specialists from Bangladesh, Brunei Darussalam, India, Indonesia, Malaysia, Philippines, Singapore, Sri Lanka, Thailand, and Viet Nam undertook to develop consensus recommendations for management and care of adults and children with obesity in South and Southeast Asia. To this end, we identified and researched 12 clinical questions related to obesity. These questions address the optimal approaches for identifying and staging obesity, treatment (lifestyle, behavioral, pharmacologic, and surgical options) and maintenance of reduced weight, as well as issues related to weight stigma and patient engagement in the clinical setting. We achieved consensus on 42 clinical recommendations that address these questions. An algorithm describing obesity care is presented, keyed to the various consensus recommendations.

Differences in weight loss outcomes for males and females on a low-carbohydrate diet: A systematic review.

It has been widely demonstrated that there are a broad range of individual responses to all weight management regimens, often masked by reports of the mean. Identifying features of responders and non-responders to weight loss regimens enables a more tailored approach to the provision of weight management advice. Low-carbohydrate diets are currently popular, and anecdote suggests that males are more successful at losing weight using this approach. This is feasible given the physiological and socio-psychological differences between the genders. We analysed the extent and variation in weight change for males and females separately through a systematic search for all low-carbohydrate diet trials published since 1985. Very few studies compared weight loss outcomes by gender and, of those that did, most lacked supporting data. The majority of studies reported no gender difference but when a gender difference was found, males were more frequently reported as losing more weight than females on a low-carbohydrate diet. The lack of gender stratification in weight loss trials is concerning, as there are a range of gender-based factors that affect weight loss outcomes. This study highlights the importance of examining weight change for males and females separately, since as failure to do so may mask any potential differences, which, if detected, could assist with better weight loss outcomes.