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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

Systems-level analysis of insulin action in mouse strains provides insight into tissue- and pathway-specific interactions that drive insulin resistance.

Skeletal muscle and adipose tissue insulin resistance are major drivers of metabolic disease. To uncover pathways involved in insulin resistance, specifically in these tissues, we leveraged the metabolic diversity of different dietary exposures and discrete inbred mouse strains. This revealed that muscle insulin resistance was driven by gene-by-environment interactions and was strongly correlated with hyperinsulinemia and decreased levels of ten key glycolytic enzymes. Remarkably, there was no relationship between muscle and adipose tissue insulin action. Adipocyte size profoundly varied across strains and diets, and this was strongly correlated with adipose tissue insulin resistance. The A/J strain, in particular, exhibited marked adipocyte insulin resistance and hypertrophy despite robust muscle insulin responsiveness, challenging the role of adipocyte hypertrophy per se in systemic insulin resistance. These data demonstrate that muscle and adipose tissue insulin resistance can occur independently and underscore the need for tissue-specific interrogation to understand metabolic disease.

The impact of weight cycling on health outcomes in animal models: A systematic review and meta-analysis.

The pattern of weight loss and regain, termed "weight cycling," is common in overweight individuals. It is unclear whether the well-established benefits of weight loss persist following weight regain or whether weight cycling is harmful. Human studies of weight cycling have conflicting results reflecting limitations of the observational designs of these studies. By controlling the macronutrient content of diets in animal studies, weight cycling can be studied in a highly controlled manner, thereby overcoming the limitations of human studies. We conducted a systematic review and meta-analysis of animal studies which assessed the health consequences of weight cycling. Studies were classified into those which compared weight cycling to lifelong obesity and those which compared weight cycling to later onset obesity. There were no differences in health outcomes between weight cycled animals and those with lifelong obesity, highlighting that weight regain reverses health benefits achieved by weight loss. In comparison with animals with later onset obesity, weight cycled animals had higher fasting glucose levels and more impaired glucose tolerance following weight regain. Our review of animal studies suggests that health benefits of diet-induced weight loss do not persist after weight regain and weight cycling results in adverse metabolic outcomes.

A sustainable development goal framework to guide multisectoral action on NAFLD through a societal approach.

BACKGROUND: Non-alcoholic fatty liver disease (NAFLD) is a highly prevalent condition that requires a comprehensive and coordinated response across sectors and disciplines. AIMS: In the absence of a multisectoral framework to tackle this condition, we developed one using the sustainable development goals (SDGs) as the basis for converging thinking about the design and delivery of public health responses. METHODS: A multidisciplinary group identified the SDG targets and indicators for inclusion in the new framework through a two-stage process. Firstly, a core team of three researchers independently reviewed the 169 targets and 231 indicators of the SDGs to select a shortlist. Over two Delphi rounds, a multidisciplinary group of 12 experts selected which of the shortlisted targets and indicators to include. Respondents also provided written feedback on their selection. Targets and indicators with 75% or greater agreement were included in the final framework. RESULTS: The final framework comprises 16 targets-representing 9% of all targets and 62% (16/26) of the shortlisted targets-and seven indicators, accounting for 50% (7/14) of the shortlisted indicators and 3% of all indicators. The selected targets and indicators cover a broad range of factors, from health, food and nutrition to education, the economy, and the built environment. CONCLUSIONS: Addressing the challenge of NAFLD will require a re-envisioning of the liver health landscape, with greater focus on joined-up systems thinking and action. This new framework can help guide this process, including by outlining the stakeholders with whom the liver health community needs to engage.

The use of SGLT2 inhibitors in achieving glycaemic control in maturity-onset diabetes of the young type 3.

SUMMARY: Maturity-onset diabetes of the young type 3 (MODY3) accounts for approximately 50% of cases of MODY. First-line treatment with sulfonylureas has been well established for individuals with MODY3. In contrast, the use of sodium-glucose co-transporter 2 (SGLT2) inhibitors in the treatment of individuals with MODY3 remains unclear. This case illustrates the in vivo effect of an SGLT2 inhibitor in a 30-year-old woman with MODY3 with poor glycaemic control despite the treatment with supramaximal doses of sulfonylurea and metformin. The addition of a SGLT2 inhibitor resulted in a rapid improvement in glycaemic control without any hypoglycaemic episodes. This case suggests that SGLT2 inhibitors may be an effective and potent treatment option in addition to sulfonylureas for individuals with MODY3. LEARNING POINTS: Maturity-onset diabetes of the young type 3 (MODY3) arises from mutations in the hepatocyte nuclear factor-1alpha gene, which controls the expression of sodium-glucose co-transporter 2 (SGLT2) in the kidneys. Paradoxically, despite individuals with MODY3 having reduced expression of SGLT2, SGLT2 inhibitors induce higher glycosuria in individuals with MODY3 compared to individuals with type 2 diabetes mellitus. SGLT2 inhibitors may be an effective treatment for achieving glycaemic control in individuals with MODY3.