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.
Despite significant reductions in serious adverse perinatal outcomes for women with type 1 diabetes in pregnancy, the opposite effect has been observed for fetal overgrowth and associated ...complications, such as neonatal hypoglycemia, shoulder dystocia, and admission to the neonatal intensive care unit. In addition, infants born large for gestational age (LGA) have an increased lifetime risk of obesity, diabetes, and chronic disease. Although exposure to hyperglycemia plays an important role, women who seemingly achieve adequate glycemic control in pregnancy continue to experience a greater risk of excess fetal growth, leading to LGA neonates and macrosomia. We review potential contributors to excess fetal growth in pregnancies complicated by type 1 diabetes. In addition to hyperglycemia, we explore the role of glycemic variability, prepregnancy overweight and obesity, gestational weight gain, and maternal lipid levels. Greater understanding of the stimuli that drive excess fetal growth could lead to targeted management strategies in pregnant women with type 1 diabetes, potentially reducing the incidence of LGA neonates and the inherent risk of acute and long-term complications.
Human adiposity has long been associated with insulin resistance and increased cardiovascular risk, and abdominal adiposity is considered particularly adverse. Intra-abdominal fat is associated with ...insulin resistance, possibly mediated by greater lipolytic activity, lower adiponectin levels, resistance to leptin, and increased inflammatory cytokines, although the latter contribution is less clear. Liver lipid is also closely associated with, and likely to be an important contributor to, insulin resistance, but it may also be in part the consequence of the lipogenic pathway of insulin action being up-regulated by hyperinsulinemia and unimpaired signaling. Again, intramyocellular triglyceride is associated with muscle insulin resistance, but anomalies include higher intramyocellular triglyceride in insulin-sensitive athletes and women (vs men). Such issues could be explained if the “culprits” were active lipid moieties such as diacylglycerol and ceramide species, dependent more on lipid metabolism and partitioning than triglyceride amount.
Subcutaneous fat, especially gluteofemoral, appears metabolically protective, illustrated by insulin resistance and dyslipidemia in patients with lipodystrophy. However, some studies suggest that deep sc abdominal fat may have adverse properties.
Pericardial and perivascular fat relate to atheromatous disease, but not clearly to insulin resistance.
There has been recent interest in recognizable brown adipose tissue in adult humans and its possible augmentation by a hormone, irisin, from exercising muscle. Brown adipose tissue is metabolically active, oxidizes fatty acids, and generates heat but, because of its small and variable quantities, its metabolic importance in humans under usual living conditions is still unclear.
Further understanding of specific roles of different lipid depots may help new approaches to control obesity and its metabolic sequelae.
Summary
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.
The Edmonton Obesity Staging System (EOSS) is based on weight related health complications among individuals with overweight and obesity requiring clinical intervention. We aimed to assess the ...clinical usefulness of a new screening tool based on the EOSS for activating weight management discussions in general practice.
We enrolled five General Practitioners (GPs) and 25 of their patients located nationwide in metropolitan areas of Australia to test the feasibility, acceptability, and accuracy of the new 'EOSS-2 Risk Tool', using cross-sectional and qualitative study designs. Diagnostic accuracy of the tool for the presence of EOSS ≥2 criteria was based on clinical information collected prospectively. To assess feasibility and applicability, we explored the views of GP and patient participants by thematic analysis of transcribed verbatim and de-identified data collected by semi-structured telephone interviews.
Nineteen (76%) patients were aged ≥45 years, five (20%) were male, and 20 (80%) were classified with obesity. All 25 patients screened positive for EOSS ≥2 criteria by the tool. Interviews with patients continued until data saturation was reached resulting in a total of 23 interviews. Our thematic analysis revealed five themes: GP recognition of obesity as a health priority (GPs expressed strong interest in and understanding of its importance as a health priority); obesity stigma (GPs reported the tool helped them initiate health based and non-judgmental conversations with their patients); patient health literacy (GPs and patients reported increased awareness and understanding of weight related health risks), patient motivation for self-management (GPs and patients reported the tool helped focus on self-management of weight related complications), and applicability and scalability (GPs stated it was easy to use, relevant to a range of their patient groups, and scalable if integrated into existing patient management systems).
The EOSS-2 Risk Tool is potentially clinically useful for activating weight management discussions in general practice. Further research is required to assess feasibility and applicability.
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.
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.
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.
At 12 months T2D remission was achieved for one in two Australian adults in a primary care setting.
Abstract 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.
Meal replacement Severely Energy-Restricted Diets (SERDs) produce ≥ 10% loss of body mass when followed for 6 weeks or longer in people with class III obesity (BMI ≥ 40 kg/m2). The efficacy of SERDs ...continues to be questioned by healthcare professionals, with concerns about poor dietary adherence. This study explored facilitators and barriers to dietary adherence and program attrition among people with class III obesity who had attempted or completed a SERD in a specialised weight loss clinic. Participants who commenced a SERD between January 2016 to May 2018 were invited to participate. Semi-structured in-depth interviews were conducted from September to October 2018 with 20 participants (12 women and 8 men). Weight change and recounted events were validated using the participants' medical records. Data were analysed by thematic analysis using line-by-line inductive coding. The mean age ± SD of participants was 51.2 ± 11.3 years, with mean ± SD BMI at baseline 63.7 ± 12.6 kg/m2. Five themes emerged from participants' recounts that were perceived to facilitate dietary adherence: (1.1) SERD program group counselling and psychoeducation sessions, (1.2) emotionally supportive clinical staff and social networks that accommodated and championed change in dietary behaviours, (1.3) awareness of eating behaviours and the relationship between these and progression of disease, (1.4) a resilient mindset, and (1.5) dietary simplicity, planning and self-monitoring. There were five themes on factors perceived to be barriers to adherence, namely: (2.1) product unpalatability, (2.2) unrealistic weight loss expectations, (2.3) poor program accessibility, (2.4) unforeseeable circumstances and (2.5) externalised weight-related stigma. This study highlights opportunities where SERD programs can be optimised to facilitate dietary adherence and reduce barriers, thus potentially improving weight loss outcomes with such programs. Prior to the commencement of a SERD program, healthcare professionals facilitating such programs could benefit from reviewing participants to identify common barriers. This includes identifying the presence of product palatability issues, unrealistic weight loss expectations, socio-economic disadvantage, and behaviour impacting experiences of externalised weight-related stigma.
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