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Purpose of Review: As obesity and chronic kidney disease (CKD) remain a public health issue, we aim to elaborate on their complex relationship regarding pathogenetic mechanisms and therapeutic potential as well. The purpose of this review is to enhance our understanding of the interplay between obesity and CKD in order to timely diagnose and treat obesity-related CKD., Recent Findings: Obesity and CKD pose significant intertwined challenges to global health, affecting a substantial portion of the population worldwide. Obesity is recognized as an independent risk factor, intricately contributing to CKD pathogenesis through mechanisms such as lipotoxicity, chronic inflammation, and insulin resistance. Recent evidence highlights additional factors including hemodynamic changes and intestinal dysbiosis that exacerbate kidney dysfunction in obese individuals, leading to histologic alterations known as obesity-related glomerulopathy (ORG). This narrative review synthesizes current knowledge on the prevalence, pathophysiology, clinical manifestations, and diagnostic strategies of obesity-related kidney disease. Furthermore, it explores mechanistic insights to delineate current therapeutic approaches, future directions for managing this condition and controversies. By elucidating the multifaceted interactions between obesity and kidney health, this review aims to inform clinical practice and stimulate further research to address this global health epidemic effectively., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: The current obesity pandemic has given rise to associated comorbidities and complications, including type 2 diabetes and metabolic dysfunction-associated steatotic liver disease (MASLD). During the last decade, certain glucagon-like peptide 1 receptor agonists (GLP-1RA), originally developed as antihyperglycemic drugs, also demonstrated efficacy for weight loss., Aims: To review shared pathophysiologic features of common metabolic diseases and compare therapeutic strategies to reduce body weight and related complications., Methods: We performed an extensive literature research to describe the effects of lifestyle modification, first-generation anti-obesity drugs, and GLP-1RA on weight loss in humans with obesity, type 2 diabetes and MASLD., Results: Until recently, treatment of obesity has been limited to lifestyle modification, which offer moderate degree and sustainability of weight loss. The few approved first-generation anti-obesity drugs are either limited to short term use or to certain forms of obesity. Some GLP-1RA significantly decrease caloric intake and body weight. Liraglutide and semaglutide have therefore been approved for treating people with obesity. They also lead to a reduction of hepatic fat content and inflammation in people with biopsy-confirmed MASLD. Possible limitations comprise adverse effects, treatment adherence and persistence., Conclusion: Certain GLP-1RA are superior to lifestyle modification and first-generation anti-obesity drugs in inducing weight loss. They have therefore markedly changed the portfolio of obesity treatment with additional beneficial effects on steatotic liver disease., (© 2024 The Authors. Alimentary Pharmacology & Therapeutics published by John Wiley & Sons Ltd.)

Introduction: Glucagon-like peptide-1 receptor agonists are novel medications with proven efficacy in treating type 2 diabetes mellitus, and are increasingly being used for weight loss. They may potentially have benefit in treating metabolic disorders; however, evidence is sparse with regards to treating high blood pressure (BP). We performed a systematic review, meta-analysis and meta-regression investigating the efficacy of GLP-1 RAs in lowering BP in obese or overweight patients., Methods: Three electronic databases (PubMed, EMBASE, and CENTRAL) were systematically searched for randomized controlled trials (RCTs) published from inception to 13 February 2024. Pair-wise meta-analysis and random effects meta-regression models were utilized. Fixed effects meta-analysis was used to unify treatment effects across different GLP-1 RA doses., Results: We included a total of 30 RCTs with a combined population of 37 072 patients. GLP-1 RAs demonstrated a mean systolic BP (SBP) reduction of -3.37 mmHg [95% confidence interval (CI) -3.95 to -2.80] and a mean diastolic BP (DBP) reduction of -1.05 mmHg (95% CI -1.46 to -0.65) compared with placebo. This effect was consistent across subgroups for diabetic status, formulation of GLP-1 RA, follow-up duration and route of administration for both SBP and DBP, with the exception of subgroups investigating exenatide. Meta-regression suggested no significant correlation between BP reduction and baseline characteristics such as age, percentage of male patients, HbA1c, weight, BMI, and percentage of patients with hypertension., Conclusion: Our meta-analysis suggests significant BP reduction benefits from GLP-1 RA use in obese or overweight patients, consistent across diabetic status, duration of treatment, and across route of administration., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Obesity and prediabetes affect a substantial part of the general population, but are largely underdiagnosed, underestimated, and undertreated. Prediabetes differs from diabetes only in the degree of hyperglycaemia consequent to the progressive decline in residual beta-cell function. Both prediabetes and diabetes occur as a consequence of insulin resistance that starts several years before the clinical onset of overt diabetes. Macrovascular complications in patients with diabetes are mainly caused by insulin resistance. This is why in prediabetes, the overall cardiovascular risk is, by all means, similar to that in patients with diabetes. It is important, therefore, to identify prediabetes and treat patients not only to prevent or delay the onset of diabetes, but to reduce the cardiovascular risk associated with prediabetes. This review provides an overview of the pathophysiology of prediabetes in patients with obesity and the progression toward overt diabetes. We have reviewed nutritional and pharmacological approaches to the management of obesity and reduced glucose tolerance, and the treatment of the major comorbidities in these patients, including hypertension, dyslipidaemia, and Metabolic dysfunction-associated Steatotic Liver Disease (MASLD), has also been reviewed. In patients with obesity and prediabetes, the nutritional approach is similar to that adopted for patients with obesity and diabetes; treatments of dyslipidaemia and hypertension also have the same targets compared to patients with diabetes. MASLD is a critical issue in these patients; in the prediabetic state, MASLD rarely progresses into fibrosis. This highlights the importance of the early recognition of this pathological condition before patients become diabetic when the risk of fibrosis is much higher. It is necessary to raise awareness of the clinical relevance of this pathological condition in order to prompt early intervention before complications occur. The single most important therapeutic goal is weight loss, which must be early and persistent., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Aim: To explore the effectiveness of the Metawell programme on cardiometabolic risk factors in China, which combines meal replacement biscuits, a wireless scale, and a mobile phone application., Methods: In this two-arm, parallel-design randomized study, 220 participants were randomly assigned to an intervention (n = 110) and a control (n = 110) group. Participants in the intervention group were instructed to use meal replacement products and scales for weight loss and monitoring, whereas participants in the control group received printed materials containing a sample diet and face-to-face weight loss education at enrolment. The trial lasted 6 months, including a weight loss period in Months 1-3 and a weight maintenance period in Months 3-6. Generalized estimating equations were used to compare differences between the two groups., Results: The median (interquartile range) ages of the intervention and control groups were 32.00 (28.00, 39.00) years and 33.00 (28.25, 41.00) years, with body mass indices of 28.20 (26.30, 30.95) kg/m 2 and 27.70 (26.02, 29.70) kg/m 2 , respectively. Participants in the intervention group experienced significantly greater decreases in waist circumference, hip circumference, triglycerides, total cholesterol: high-density lipoprotein cholesterol ratio, fasting blood glucose, fasting insulin, and homeostatic model assessment of insulin resistance index compared to the control group (p < 0.01). Among participants who did not regain weight during the maintenance period after weight loss, the reductions in systolic and diastolic blood pressure were significantly greater in the intervention group than in the control group (p < 0.05)., Conclusions: The Metawell programme of caloric restriction and remote monitoring can be adapted to overweight and obese people in China to reduce their cardiometabolic risk factors. Furthermore, there was a better improvement in blood pressure in participants who maintained the effects of weight loss., (© 2024 The Author(s). Diabetes, Obesity and Metabolism published by John Wiley & Sons Ltd.)

Lipotoxicity, originally used to describe the destructive effects of excess fat accumulation on glucose metabolism, causes functional impairments in several metabolic pathways, both in adipose tissue and peripheral organs, like liver, heart, pancreas, and muscle. Ectopic lipid accumulation in the kidneys, liver, and heart has important clinical counterparts like diabetic nephropathy in type 2 diabetes mellitus, obesity-related glomerulopathy, nonalcoholic fatty liver disease, and cardiomyopathy. Insulin resistance due to lipotoxicity indirectly lead to reproductive system disorders, like polycystic ovary syndrome. Lipotoxicity has roles in insulin resistance and pancreatic beta-cell dysfunction. Increased circulating levels of lipids and the metabolic alterations in fatty acid utilization and intracellular signaling have been related to insulin resistance in muscle and liver. Different pathways, like novel protein kinase c pathways and the JNK-1 pathway, are involved as the mechanisms of how lipotoxicity leads to insulin resistance in nonadipose tissue organs, such as liver and muscle. Mitochondrial dysfunction plays a role in the pathogenesis of insulin resistance. Endoplasmic reticulum stress, through mainly increased oxidative stress, also plays an important role in the etiology of insulin resistance, especially seen in non-alcoholic fatty liver disease. Visceral adiposity and insulin resistance both increase the cardiometabolic risk, and lipotoxicity seems to play a crucial role in the pathophysiology of these associations., (© 2024. The Author(s), under exclusive license to Springer Nature Switzerland AG.)

Purpose of Review: Cardiovascular disease (CVD) is the leading cause of death globally and is closely associated with obesity and type 2 diabetes mellitus (T2DM). This review examines the interplay between obesity, T2DM, and CVD, highlighting the increasing prevalence and economic burden of these conditions., Recent Findings: Pharmacologic therapies, particularly glucagon-like peptide-1 receptor agonists, show promise in substantial weight loss and subsequent reduction of adverse cardiovascular events in obese individuals with and without diabetes. Obesity significantly contributes to the development of insulin resistance and T2DM, further escalating CVD risk. The common co-occurrence of these three conditions may involve several other pathophysiological mechanisms, such as chronic inflammation, increased visceral adiposity, and endothelial dysfunction. Until recently, lifestyle modifications and bariatric surgery had been the primary methods for weight loss and mitigating obesity-associated cardiovascular risk. Newer pharmacological options have led to a paradigm shift in our approach to obesity management as they provide substantial benefits in weight loss, glycemic control, and cardiovascular risk reduction., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Purpose of Review: Body fat distribution plays a significant role in the cardiometabolic consequences of obesity. We review the impact of visceral and hepatic fat and highlight important interventions., Recent Findings: Several epidemiologic studies have established a clear association between visceral fat and cardiovascular disease. The association between hepatic fat and cardiovascular disease is less clear with discordant results. Novel evidence demonstrates sodium glucose co-transporter-2 (SGLT2) inhibitors facilitate modest weight loss and reductions in ectopic fat depots in patient with type 2 diabetes. Glucagon-like peptide-1 (GLP-1) receptor agonists have been associated with decreased visceral/hepatic fat and reductions in MACE in populations with type 2 diabetes and with overweight/obesity. Clear associations between visceral fat and cardiometabolic outcomes have been established, whereas the impact of hepatic fat remains less clear. Lifestyle modification and pharmacologic interventions remain the initial therapies, while surgical intervention is associated with improved long-term outcomes. Emerging therapies have demonstrated a profound impact on body fat distribution and cardiometabolic risk., (© 2024. The Author(s).)

Introduction: Maternal overweight or obesity has been associated with metabolic syndrome through 1 year postpartum, but it remains unknown whether a culturally-modified, motivationally-targeted, and individually-tailored Lifestyle Intervention could improve postpartum cardiometabolic health among Hispanic women with overweight or obesity., Methods: Proyecto Mamá was a randomized controlled trial conducted in Western Massachusetts from 2014 to 2020 in which Hispanic women with overweight/obesity were randomized to a Lifestyle Intervention (LI) involving diet and exercise or to a comparison Health and Wellness Intervention (HW). Biomarkers of cardiovascular risk (i.e., lipids, C-reactive protein) and insulin resistance (fasting insulin, glucose, HbA1c, homeostasis model assessment [HOMA-IR], leptin, adiponectin) were measured at baseline (early pregnancy), mid-pregnancy, and 6 weeks, 6 months, and 12 months postpartum. Generalized linear mixed effect models were used to evaluate differences in the change in biomarkers over the course of postpartum follow-up time., Results: In intent-to-treat analyses among eligible women (LI; n=51, HW; n=58) there were no significant differences in changes in biomarkers of CVD risk or insulin resistance over the postpartum year; for example, the intervention effect for total cholesterol was 6.98 (SE: 6.36, p=0.27) and for HbA1c was -0.01 (SE: 0.4, p=0.85). In pooled analyses, regardless of intervention arm, women who participated in any vigorous activity had less of an increase in HbA1c (intervention effect = -0.17, SE: 0.05, p=0.002) compared to those with no vigorous activity, and similarly beneficial associations with other cardiovascular risk biomarkers (p<0.05)., Discussion: Women who participated in vigorous activity, regardless of their assigned intervention arm, had more favorable changes in biomarkers of insulin resistance., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Semaglutide is found to be efficient for weight loss in patients with overweight or obesity with diabetes mellitus (DM). With a wide range of adverse events reported, the efficacy and safety of once-weekly subcutaneous semaglutide in individuals without DM, with overweight or obesity, is unclear. We conducted a comprehensive meta-analysis of randomized studies on once-weekly semaglutide in this patient population. We identified nine studies with 11,641 patients in the semaglutide group and 10,479 in the placebo group. We observed that semaglutide resulted in significant benefits, including change in body weight (%): mean difference (MD) of -11.49% (p < 0.0001), change in absolute body weight: MD of -11.74 kg (p < 0.0001), and change in waist circumference: MD of -9.06 cm (p < 0.0001). Gastrointestinal side effects are predominant including nausea: odds ratio (OR) of 4.06 (p < 0.0001), vomiting: OR of 4.43 (p < 0.0001), diarrhea: OR of 2.10 (p < 0.0001), constipation: OR of 2.43 (p < 0.0001), gallbladder disorders: OR of 1.26 (p = 0.010), and cholelithiasis: OR of 2.06 (p = 0.04). Serious adverse events were not statistically significant: OR of 1.06 (p = 0.82). However, the percentage of participants discontinuing due to adverse events and gastrointestinal side effects was statistically significant: ORs of 2.22 (p < 0.0001) and 3.77 (p < 0.0001), respectively. This study shows that in patients with overweight or obesity without DM, once-weekly subcutaneous semaglutide can significantly decrease body weight without risk of serious adverse events when compared with a placebo. However, gastrointestinal side effects are predominant with semaglutide, which can result in medication discontinuation., (© 2024 The Author(s). Obesity Reviews published by John Wiley & Sons Ltd on behalf of World Obesity Federation.)

White adipose tissue accumulation and inflammation contribute to obesity by inducing insulin resistance. Herein, we aimed to screen the synergistic components of the herbal pair Coptidis Rhizoma-Glycyrrhizae Radix et Rhizoma for the treatment of insulin resistance and explore the potential synergistic mechanisms. Enzyme-linked immunosorbent assay and quantitative PCR were used to detect expression levels of inflammatory genes in vitro and in vivo. Western blotting and immunohistochemistry were performed to detect protein levels of the insulin signaling pathway and macrophage markers. The effects on obesity-induced insulin resistance were verified using a diet-induced obesity (DIO) mouse model. Interactions between macrophage and adipocyte were assessed using a cellular supernatant transfer assay. Berberine (BBR) and isoliquiritigenin (ISL) alleviated mRNA levels and secretion of inflammatory genes in vitro and in vivo. Furthermore, BBR acted synergistically with ISL to ameliorate obesity and dyslipidemia in DIO mice. Meanwhile, the combination treatment significantly improved glucose intolerance and insulin resistance and decreased M1-macrophage accumulation and infiltration in the adipose tissue. Mechanistically, co-treatment with BBR and ISL upregulated the protein expression of the IRS1-PI3K-Akt insulin signaling pathway, enhanced glucose uptake in adipocyte, and suppressed the interaction between macrophage and adipocyte. BBR and ISL were identified as the synergistic components of the herbal pair Coptidis Rhizoma-Glycyrrhizae Radix et Rhizoma for treating insulin resistance. The synergistic combination of BBR with ISL can be a promising and effective strategy for improving obesity-induced adipose inflammation and insulin resistance., (© 2024 John Wiley & Sons Ltd.)

Aims: To assess the excess risk of cardiovascular disease (CVD) associated with different criteria for metabolic health, and the interplay of body size, insulin sensitivity and metabolic health with CVD risk., Materials and Methods: We conducted a prospective study involving 115 638 participants from the China Cardiometabolic Disease and Cancer Cohort (4C) Study. Metabolic health was defined using three different definitions: (1) insulin sensitivity defined by homeostatic model assessment of insulin resistance index; (2) absence of metabolic syndrome according to the National Cholesterol Education Program Adult Treatment Panel III criteria; and (3) simultaneous absence of metabolic abnormalities (diabetes, hypertension, dyslipidaemia). The primary endpoint was a composite of incident CVD events comprising the first occurrence of myocardial infarction, stroke, heart failure, or cardiovascular death., Results: During a mean 3.61-year follow-up period, obese individuals with insulin sensitivity (multivariable-adjusted hazard ratio [HR] 1.69, 95% confidence interval [CI] 1.37-2.08), or without metabolic syndrome (HR 1.46, 95% CI 1.13-1.89) still exhibited increased CVD risks, when compared to their normal-weight counterparts. Otherwise, those with obesity but simultaneous absence of metabolic abnormalities demonstrated similar CVD risk compared to normal-weight individuals (HR 0.91, 95% CI 0.53-1.59). CVD risk increased with the number of abnormalities across body mass index categories, regardless of insulin sensitivity., Conclusions: This study emphasizes the need for refined definitions of metabolic health and advocates for meticulous screening for metabolic abnormalities to reduce cardiovascular risks, even in individuals with normal weight and insulin sensitivity., (© 2024 The Authors. Diabetes, Obesity and Metabolism published by John Wiley & Sons Ltd.)

Aim: To evaluate the effect of metformin on cancer incidence in subjects with overweight/obesity and/or prediabetes/diabetes., Materials and Methods: We searched MEDLINE, Embase and CENTRAL for randomized controlled trials (RCTs) in adults with overweight/obesity and/or prediabetes/diabetes that compared metformin to other interventions for ≥24 weeks. Independent reviewers selected and extracted data including population and intervention characteristics and new diagnoses of cancer. We used the RoB 2.0 risk-of-bias tool and the Grading of Recommendations, Assessment, Development and Evaluations (GRADE) framework to assess risk of bias and certainty of evidence., Results: From 14 895 records after removal of duplicates, 27 trials were included, providing a total of 10 717 subjects in the metformin group and 10 003 in the control group, with 170 and 208 new cases of cancer, respectively. Using a random-effects model, the relative risk was 1.07 (95% confidence interval 0.87-1.31), with similar results in subgroup analyses by study duration or effect of control intervention on weight. Risk of bias in most studies was low, and no evidence of publication bias was found. Trial sequential analysis provided evidence that the cumulative sample size was large enough to exclude a significant effect of metformin on cancer incidence., Conclusions: Metformin did not reduce cancer incidence in RCTs involving subjects with overweight/obesity and/or prediabetes/diabetes., (© 2024 John Wiley & Sons Ltd.)

Increase in the prevalence of obesity has become a major worldwide health problem in adults as well as among children and adolescents. In the last four decades, studies have revealed that the significant increase in the prevalence of obesity has become a pandemic. Obesity is the result of complex interactions between biological, genetic, environmental, and behavioral factors. Indeed, almost all of the children suffering from obesity in early childhood face with being overweight or obese in adolescence. Different phenotypes have different risk factors in the clinical evaluation of obesity. Individuals suffering from metabolically unhealthy obesity (MUO) are at an excess risk of developing cardiovascular diseases (CVDs), several cancer types, and metabolic syndrome (MetS), whereas the metabolically healthy obesity (MHO) phenotype has a high risk of all-cause mortality and cardiometabolic events but not MetS. While most obese individuals have the MUO phenotype, the frequency of the MHO phenotype is at most 10-20%. Over time, approximately three-quarters of obese individuals transform from MHO to MUO. Total adiposity and truncal subcutaneous fat accumulation during adolescence are positively and independently associated with atherosclerosis in adulthood. Obesity, in general, causes a large reduction in life expectancy. However, the mortality rate of morbid obesity is greater among younger than older adults. Insulin resistance (IR) develops with the central accumulation of body fat. MHO patients are insulin-sensitive like healthy normal-weight individuals and have lower visceral fat content and cardiovascular consequences than do the majority of MUO patients. MetS includes clustering of abdominal obesity, dyslipidemia, hyperglycemia, and hypertension. The average incidence of MetS is 3%, with a 1.5-fold increase in the risk of death from all causes in these patients. If lifestyle modifications, dietary habits, and pharmacotherapy do not provide any benefit, then bariatric surgery is recommended to reduce weight and improve comorbid diseases. However, obesity treatment should be continuous in obese patients by monitoring the accompanying diseases and their consequences. In addition to sodium-glucose co-transporter-2 (SGLT2) inhibitors, the long-acting glucagon-like peptide-1 (GLP-1) receptor agonist reduces the mean body weight. However, caloric restriction provides more favorable improvement in body composition than does treatment with the GLP-1 receptor (GLP1R) agonist alone. Combination therapy with orlistat and phentermine are the US Food and Drug Administration (FDA)-approved anti-obesity drugs. Recombinant leptin and synthetic melanocortin-4-receptor agonists are used in rarely occurring, monogenic obesity, which is due to loss of function in the leptin-melanocortin pathway., (© 2024. The Author(s), under exclusive license to Springer Nature Switzerland AG.)

Background: As ethnicity is typically recorded as a single demographic variable in clinical studies, little is known about the relative impact of maternal vs. paternal ethnicity on fat distribution., Objectives: The objective of this study was to determine whether there is a differential impact of maternal and paternal ethnicity on infant adiposity., Methods: Three hundred fifty-five infants underwent anthropometric assessment at age 3 months, including skin-fold thickness (SFT) measurement at subscapular, suprailiac and triceps. Maternal (M) and paternal (P) ethnicity were classified as white (M = 241, P = 252), Asian (M = 50, P = 42) or other (M = 64, P = 61)., Results: Infants with either Asian mother (compared with white) or Asian father (compared with white) had increased subscapular, suprailiac and triceps SFT (all P < 0.05). On logistic regression analysis, however, only maternal Asian ethnicity (compared with white) independently predicted the likelihood of an infant being in the highest tertile for SFT at subscapular (odds ratio [OR] = 2.72, 95% confidence interval 1.17-6.34, P = 0.02), suprailiac (OR = 3.56, 1.51-8.42, P = 0.004) and triceps (OR = 3.26, 1.40-7.55, P = 0.005). In contrast, paternal Asian ethnicity was independently associated with sum of SFT only (OR = 2.46, 1.02-5.97, P = 0.04)., Conclusion: Maternal and paternal Asian ethnicity have differential effects on infant fat distribution. Future clinical studies on obesity and fat composition should consider the distinct contributions of both parents to the ethnic classification of participants., (© 2015 World Obesity.)

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., (© 2023. The Author(s).)

Diabesity is a term used to describe the combined adverse health effects of obesity and diabetes mellitus. The worldwide dual epidemic of obesity and type 2 diabetes is an important public health issue. Projections estimate a sixfold increase in the number of adults with obesity in 40 years and an increase in the number of individuals with diabetes to 642 million by 2040. Increased adiposity is the strongest risk factor for developing diabetes. Early detection of the effects of diabesity on the cardiovascular system would enable the optimal implementation of effective therapies that prevent atherosclerosis progression, cardiac remodelling, and the resulting ischaemic heart disease and heart failure. Beyond conventional imaging techniques, such as echocardiography, CT and cardiac magnetic resonance, novel post-processing tools and techniques provide information on the biological processes that underlie metabolic heart disease. In this Review, we summarize the effects of obesity and diabetes on myocardial structure and function and illustrate the use of state-of-the-art multimodality cardiac imaging to elucidate the pathophysiology of myocardial dysfunction, prognosticate long-term clinical outcomes and potentially guide treatment strategies.

Aim: To characterize healthcare resource (HCRU) and medication use and associated costs in individuals with obesity compared with individuals with normal weight or overweight in a population-based cohort of Finnish adults. The association between metabolic state and direct costs was also assessed., Methods: The study cohort included 5587 randomly selected individuals who participated in the national FinHealth 2017 health examination survey. Data on healthcare visits and hospital stays, including diagnoses (ICD-10), and purchases and costs of prescription medicines were collected from the nationwide registers by the Finnish Institute for Health and Welfare and Social Insurance Institution of Finland. The healthcare costs were calculated based on standard unit costs reported by the Finnish Institute for Health and Welfare., Results: The total annual direct costs were €2665 (SD €5673) and €1799 (SD €3874) per person with obesity and with normal weight or overweight, respectively. Obesity was associated with significantly increased total direct (age- and sex-adjusted cost rate ratio, RR, 1.356; p < 0.001), HCRU-related (1.273; p = 0.002), and medication (1.669; p < 0.001) costs. A vast majority (90%) of individuals with obesity were classified as metabolically unhealthy based on clinical measurements. The metabolically unhealthy state was associated with increased costs in individuals with obesity but not in individuals with normal weight or overweight., Conclusion: Obesity is associated with a significant and complex direct cost burden to society, arising primarily from increased comorbidity. Metabolically healthy obesity is uncommon and obesity prevention and timely treatment should be of high priority to tackle the increasing burden of obesity., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Background: Recent interest has focused on a unique subgroup of overweight and obese individuals who have normal metabolic features despite increased adiposity. Normal-weight individuals with adverse metabolic status have also been described. However, it remains unclear whether metabolic phenotype modifies the morbidity and mortality associated with higher body mass index (BMI)., Purpose: To determine the effect of metabolic status on all-cause mortality and cardiovascular events in normal-weight, overweight, and obese persons., Data Sources: Studies were identified from electronic databases., Study Selection: Included studies evaluated all-cause mortality or cardiovascular events (or both) and clinical characteristics of 6 patient groups defined by BMI category (normal weight/overweight/obesity) and metabolic status (healthy/unhealthy), as defined by the presence or absence of components of the metabolic syndrome by Adult Treatment Panel III or International Diabetes Federation criteria., Data Extraction: Two independent reviewers extracted the data. Metabolically healthy people of normal weight made up the reference group., Data Synthesis: Eight studies (n = 61 386; 3988 events) evaluated participants for all-cause mortality and/or cardiovascular events. Metabolically healthy obese individuals (relative risk [RR], 1.24; 95% CI, 1.02 to 1.55) had increased risk for events compared with metabolically healthy normal-weight individuals when only studies with 10 or more years of follow-up were considered. All metabolically unhealthy groups had a similarly elevated risk: normal weight (RR, 3.14; CI, 2.36 to 3.93), overweight (RR, 2.70; CI, 2.08 to 3.30), and obese (RR, 2.65; CI, 2.18 to 3.12)., Limitation: Duration of exposure to the metabolic-BMI phenotypes was not described in the studies and could partially affect the estimates., Conclusion: Compared with metabolically healthy normal-weight individuals, obese persons are at increased risk for adverse long-term outcomes even in the absence of metabolic abnormalities, suggesting that there is no healthy pattern of increased weight., Primary Funding Source: Intramural funds from the Leadership Sinai Centre for Diabetes.

Purpose of Review: Obesity is increasing in prevalence among patients with type 1 diabetes (T1D) and is associated with insulin resistance and increased cardiovascular risk. The management of obesity in this population is complicated by defects in pancreatic islet hormone secretion and the effects of exogenous insulin treatment. Here, we review the effects of antiobesity medications and adjunct-to-insulin medications on body weight in T1D., Recent Findings: There is a profound evidence gap around the use of drugs for the treatment of obesity in T1D since systematic studies have not been performed in this population. Adjunctive-to-insulin therapy with certain antihyperglycemic agents leads to modest weight loss and reductions in insulin dose in T1D. However, only pramlintide has been approved in the United States for clinical use as adjunctive therapy in T1D., Summary: The growing prevalence of obesity in T1D has created an unmet need for safe and effective therapies to treat overweight and obesity in this population. Currently, antiobesity medications are used off-label for the treatment of patients with T1D. Additional studies are needed to understand the role of these medications in the management of obesity in patients with T1D.

Moderate-to-vigorous intensity physical activity (MVPA) and obesity play important roles in the development of type 2 diabetes mellitus (T2DM) among women with prior gestational diabetes mellitus (GDM). Yet, how MVPA affects the risk of developing T2DM among women with prior GDM across the different categories of obesity indicators is unclear. This study aimed to describe the levels of postpartum abnormal glucose tolerance (AGT), obesity indicators (body mass index [BMI] and waist circumference [WC]), and MVPA and to explore the independent effect and joint effect of MVPA and obesity indicators (BMI and WC) on the risk for developing AGT among women with prior GDM in rural China. A total of 425 women with prior GDM were recruited from two county-level hospitals in Western and Eastern Hunan, China. Data were collected with self-reported measurements on sociodemographics and clinical factors as well as postpartum weight-related behaviors (physical activity and dietary intake). The 75-g oral glucose tolerance test, weight, height, and WC were measured on site. Binary logistic regression models and multiplitive interaction models were used to explore the independent and joint associations of BMI and MVPA as well as WC and MVPA on AGT, respectively. One-fifth (20.9%) of the sample women had AGT. The obesity indicators were significantly associated with an increased risk of postpartum AGT, but MVPA was not. In joint effect analyses, larger WC and insufficient MVPA were not significantly associated with increased risk of AGT compared with normal WC and sufficient MVPA (mutually adjusted odds ratio [OR], 1.43; 95% confidence interval [CI], 0.46-4.43; p > .05). In joint effect analyses of MVPA and BMI, the mutually adjusted OR for developing AGT in women who were obese and had insufficient MVPA was 4.49 (95% CI, 1.35-14.92; p < .05) compared with normal weight and sufficient MVPA. Adequate weight management and increased MVPA are warranted for Chinese women with prior GDM to prevent T2DM., (© 2020 Wiley Periodicals LLC.)

Apolipoprotein (apo) C-I is a constituent of chylomicrons, very low density lipoprotein, and high density lipoprotein. The role of apo C-I in human metabolism is incompletely defined. We took advantage of a naturally occurring amino acid polymorphism that is present in aboriginal North Americans, namely apo C-I T45S. We assessed the hypothesis that metabolic traits, including obesity-related and lipoprotein-related traits, would differ between carriers and noncarriers of apo C-I T45S. A genotyping assay was developed for APOC1 T45S and genotypes were determined in a sample of 410 Canadian Oji-Cree subjects. The allele frequency of the apo C-I S45 allele was approximately 8% in this sample. We observed the apo C-I S45 allele was significantly associated with 1) lower percent body fat (P < 0.05), 2) lower waist circumference (P = 0.058), 3) lower serum leptin levels (P < 0.05), and 4) lower plasma apo C-I levels (P < 0.0001), using a newly developed ELISA-based method. Taken together, these results suggest that at the whole human phenotype level, apo C-I is associated with the complex metabolic trait of obesity as well as with serum leptin levels.

Emerging evidence suggests that fetal environmental exposures impact on future development of obesity. The objectives of this study were to assess the relationships between (i) maternal insulin sensitivity and glucose tolerance status in pregnancy and (ii) early infant weight gain and adiposity in the first year of life. In this prospective cohort study, 301 women underwent oral glucose tolerance testing for assessment of glucose tolerance status and insulin sensitivity (IS(OGTT)) in pregnancy. Their infants underwent anthropometric assessment at 12 months of age, including determination of weight gain in the first year of life and sum of skinfold thickness (SFT), a measure of infant adiposity. Infant weight gain and sum of SFT at 12 months did not differ according to maternal glucose tolerance status. On univariate analyses, weight gain from 0 to 12 months and sum of SFT were negatively associated with maternal IS(OGTT) during pregnancy. On multiple linear regression analysis, negative independent predictors of weight gain from 0 to 12 months were maternal IS(OGTT) during pregnancy (t = -2.73; P = 0.007), infant female gender (t = -3.16; P = 0.002), and parental education (t = -1.98; P = 0.05), whereas white ethnicity was a positive independent predictor (t = 2.68; P = 0.008). Maternal IS(OGTT) (t = -2.7; P = 0.008) and parental education (t = -2.58; P = 0.01) were independent negative predictors of sum of SFT at 12 months. Independent of maternal glucose tolerance status, maternal insulin resistance during pregnancy is associated with increased infant weight gain and adiposity over the first year of life. Further longitudinal study to evaluate obesity in this group of children will increase our understanding of the contribution of the intrauterine environment to their long-term health.

Objective: Pregnant women with an abnormal screening glucose challenge test (GCT) but without gestational diabetes mellitus (GDM) on subsequent oral glucose tolerance test (OGTT) are at increased risk of delivering macrosomic and large for gestational age (LGA) neonates. We thus sought to evaluate the maternal constitutional and biochemical factors that determine infant birth weight in this patient population., Methods: Women with an abnormal GCT were evaluated at the time of their OGTT in late pregnancy. This analysis was restricted to Caucasian women without GDM (N = 86). Maternal demographic and biochemical factors were evaluated in relation to infant birth weight and LGA., Results: After adjustment for length of gestation, birth weight was positively associated with pre-pregnancy body mass index (BMI) (r = 0.31, p = 0.0063) and negatively correlated with maternal serum levels of the insulin-sensitizing protein adiponectin (r = -0.30, p = 0.0084). On multiple linear regression analysis, pre-pregnancy BMI and weight gain in pregnancy were positive independent determinants of infant birth weight, while family history of diabetes emerged as a negative independent correlate. Logistic regression analysis confirmed that pre-pregnancy BMI was a positive predictor of LGA (odds ratio (OR) = 1.25, 95% confidence interval (CI) 1.05-1.49), whereas family history of diabetes was again identified as a negative determinant (OR = 0.10, 95% CI 0.02-0.59). In contrast, neither measures of glycemia nor insulin resistance/sensitivity were independently associated with birth weight or LGA., Conclusion: In pregnant women with an abnormal GCT but without GDM, pre-gravid maternal obesity predicts increased infant birth weight, whereas family history of diabetes is independently associated with decreased infant size.

Aim: Subclinical inflammation has been proposed as a pathophysiologic mechanism linking obesity with vascular and metabolic disease. Native North American populations are experiencing high prevalence rates of both (i) childhood obesity and (ii) adult cardiovascular disease (CVD) and type 2 diabetes. Thus, we sought to determine whether subclinical inflammation is an early complication of obesity in Native children., Methods: Serum concentrations of the inflammatory biomarker C-reactive protein (CRP) were assessed in a population-based, cross-sectional study of the Sandy Lake Oji-Cree community of Northern Ontario, Canada, involving 228 children aged 10-19 years (mean age 14.8)., Results: Median CRP in this population was 0.5 mg/l (interquartile range 0.18-1.79 mg/l). CRP levels were higher than age-matched reference data from the Third National Health and Nutrition Examination Survey (NHANES III). Importantly, fully 15.8% of the children of this community had CRP concentrations between 3 and 10 mg/l, a range that identifies adults at high risk of CVD. Moreover, increasing CRP concentration in this paediatric population was associated with an enhanced CV risk profile, consisting of increased adiposity, higher insulin resistance, worsening lipid profile (higher total cholesterol, triglycerides, low-density lipoprotein cholesterol, apolipoprotein B and total cholesterol : high-density-lipoprotein cholesterol ratio), increased leptin and decreased adiponectin. On multivariate analysis, waist circumference and interleukin-6 (IL-6) emerged as independent determinants of CRP concentration., Conclusion: Subclinical inflammation is an early complication of childhood obesity in Native children and may foreshadow an increased burden of CVD and type 2 diabetes in the future.

The inflammatory factor C-reactive protein (CRP) and the fibrinolytic variables fibrinogen and plasminogen activator-1 (PAI-1) are associated with long-term cardiovascular morbidity. To determine the contribution of body adiposity (BMI), insulin sensitivity (homeostasis model assessment of insulin resistance [HOMA-IR], and glycemia (HbA(1c) [A1C]) to the levels of these inflammatory and fibrinolytic variables in recently diagnosed (

Context: Women of Asian and South Asian descent are at increased risk of developing gestational diabetes mellitus compared with Caucasians, despite lower body mass index (BMI). Nevertheless, there has been limited study of insulin action during pregnancy in these ethnic groups., Objective: The objective of the study was to compare insulin sensitivity in pregnancy in Asian, South Asian, and Caucasian subjects and to determine whether the impact of obesity on insulin action is modified by ethnicity., Design and Participants: A cross-sectional study was performed in outpatients undergoing oral glucose tolerance testing in late pregnancy. Participants were stratified into three groups: 1) Caucasian (n = 116); 2) South Asian (n = 31); and 3) Asian (n = 28)., Main Outcome Measure: Insulin sensitivity was measured using the oral glucose tolerance test (IS(OGTT)) index of M. Matsuda and R. DeFronzo, previously validated in pregnancy., Results: There were no significant ethnic differences in insulin sensitivity despite variation in prepregnancy BMI (Caucasians, 25.2 kg/m(2); South Asians, 23.3 kg/m(2); Asians, 21.4 kg/m(2); overall P = 0.0001). On multiple linear regression analysis, the strongest independent determinants of IS(OGTT) were gestational diabetes mellitus (t = -5.71; P < 0.0001) and BMI (t = -5.43; P < 0.0001). Importantly, both Asian (t = -2.87; P = 0.0047) and South Asian (t = -2.46; P = 0.015) ethnicity also emerged as negative, independent determinants of IS(OGTT). Furthermore, Asian ethnicity significantly modified the association of prepregnancy BMI with IS(OGTT) (interaction term, t = -2.29; P = 0.0231)., Conclusions: Asian and South Asian ethnicity are both independently associated with increased insulin resistance in late pregnancy. Prepregnancy BMI has a much greater effect on insulin resistance in pregnancy in Asian women than in Caucasians. Ethnicity thus emerges as a factor that modulates the effect of obesity on insulin resistance in pregnancy.

Objective: Adiponectin is emerging as an important protein in the etiology of obesity and related metabolic disorders. The objectives of this study were to determine cross-sectional and prospective associations of adiponectin concentration with adiposity, type 2 diabetes, and cardiovascular disease (CVD) risk factors in a population-based study of Native Canadians, a group experiencing dramatic increases in diabetes and CVD., Research Design and Methods: During the 1993-1995 baseline survey, samples for glucose, insulin, adiponectin, and lipids were collected after an overnight fast. Waist circumference and percent body fat were measured, and a 75-g oral glucose tolerance test was administered: n = 505 with normal glucose tolerance (NGT), 74 with impaired glucose tolerance (IGT), and 149 with diabetes. In 1998, 95 high-risk subjects, defined as those who, at baseline, had either IGT or NGT with an elevated 2-h glucose concentration (>/==" BORDER="0">7.0 mmol/l), participated in a follow-up examination using the protocol used at baseline., Results: After adjustment for covariates including percent body fat and homeostasis model assessment of insulin resistance (HOMA-IR), adiponectin concentrations were significantly lower among men versus women (10.8 vs. 15.0 micro g/ml, P < 0.0001) and among diabetic versus NGT subjects (11.1 vs. 13.1 micro g/ml, P < 0.05). Adiponectin was inversely correlated with percent body fat, waist circumference, HOMA-IR, and triglyceride and positively correlated with HDL (r = |0.30|-|0.44|, all P < 0.0001). In multivariate linear regression analysis in nondiabetic subjects, HDL and percent body fat were significantly related to adiponectin variation among both men and women (R(2) = 28-29%). Factor analysis returned three underlying factors among these variables, with adiponectin loading on the second factor along with insulin, waist circumference, triglyceride, and HDL. In the follow-up study, higher adiponectin at baseline was significantly associated with increases in HDL (r = 0.24, P = 0.03) and decreases in HOMA-IR (r = -0.29, P = 0.009) after adjustment for covariates, including age, adiposity, and diabetes status at baseline and follow-up., Conclusions: These population-based findings support the hypothesis that low circulating levels of adiponectin are an important determinant of risk of CVD.

Acute-phase biomarkers such as C-reactive protein (CRP) and IL-6 have emerged as predictors of incident type 2 diabetes mellitus, implicating chronic subclinical inflammation as a factor in the pathophysiology of diabetes. Gestational diabetes (GDM) identifies a population of women at high risk of subsequent type 2 diabetes mellitus, representing an early stage in the natural history of the disease. In this context, we performed a cross-sectional study to determine whether markers of subclinical inflammation are elevated in patients with GDM. We studied 180 healthy pregnant women undergoing oral glucose tolerance testing in the late second or early third trimester. Based on oral glucose tolerance testing and prepregnancy body mass index (BMI), participants were stratified into four groups: 1) normal glucose tolerance (NGT) lean (BMI, <25 kg/m(2)) (n = 65); 2) NGT overweight (n = 28); 3) impaired glucose tolerance (n = 39); and 4) GDM (n = 48). Median CRP level was highest in overweight NGT subjects (8.8 mg/liter), followed by GDM (5.5 mg/liter), impaired glucose tolerance (4.4 mg/liter), and lean NGT (4.4 mg/liter) (overall P = 0.0297). CRP was significantly correlated with prepregnancy BMI (r = 0.38, P < 0.0001), followed by fasting insulin (r = 0.27, P = 0.0002) and fasting blood glucose (r = 0.18, P = 0.016). In multivariate linear regression analysis, prepregnancy BMI emerged as the most important determinant of CRP concentration, whereas glycemic tolerance status was not a significant factor. Furthermore, the observed stepwise increase in CRP per tertile of prepregnancy BMI was not significantly attenuated by glycemic tolerance status or factors known to be associated with GDM. In summary, we demonstrate that maternal serum levels of CRP are not related to GDM but rather correlate significantly with prepregnancy obesity. An independent contribution of CRP to risk of GDM could not be confirmed. These data suggest a model in which obesity mediates a systemic inflammatory response, with possible downstream metabolic sequelae, including insulin resistance and glucose dysregulation.

Objective: To determine the prevalence of elevated C-reactive protein (CRP) in the Sandy Lake Oji-Cree, an aboriginal community residing in the Sioux Lookout zone of Northwestern Ontario, Canada, and to determine the associations of obesity and diabetes with CRP in a community with a very high prevalence of type II diabetes., Design: We surveyed 512 community members aged 18 y and older to determine the prevalence and the determinants of elevated CRP in Sandy Lake., Measurements: Clinical variables, indices of obesity and serum concentrations of CRP, insulin, serum amyloid A (SAA) and interleukin-6 (IL-6)., Results: The prevalence of CRP >or=3.8 mg/l was significantly higher in women than in men (51% vs. 32%, P<0.0001). Regression analysis determined that body mass index and IL-6 were independent determinants of CRP concentration in women and waist circumference and IL-6 were independent determinants of CRP concentration in men. Diabetes was associated with elevated CRP in both sexes, but was only a moderate strong determinant in CRP concentration in multivariate regression analysis., Conclusions: The prevalence of elevated CRP in this aboriginal community is remarkably high. These data further demonstrate that the association between CRP and specific indices of obesity and metabolism vary according to gender and glycemic status.

Background: This study determined the relationship between physical activity (PA), circulating lipids throughout pregnancy and infant anthropometric outcomes at birth and 2 weeks of age., Methods: Women (N = 234) with normal weight (NW, BMI 18.5-24.9 kg/m 2 ) and with overweight and class I obesity (OW/OB, BMI 25-35 kg/m 2 ) were categorized into high and low PA based on average cohort steps during pregnancy (8099 steps/day). Circulating fasting lipids were measured at each trimester. Standardized methods were used to obtain anthropometrics measures. Infant body composition was estimated by quantitative nuclear magnetic resonance (EchoMRI-AH small; ECHO Medical Systems)., Results: Women with NW who had higher activity had lower circulating triglycerides (TG) and total cholesterol (TC) levels at 12 weeks compared to women with NW and low activity (p < 0.05). Women with OW/OB and high activity level throughout pregnancy had lower circulating TG, and low density lipoprotein (LDL), at 12 weeks, lower LDL at 24 weeks, and lower TG at 36 weeks compared to the women with OW/OB who had low activity levels (p < 0.05). For children born to women with OW/OB, maternal circulating TG and LDL were most associated with infant anthropometrics at 2 weeks of age., Conclusion: This study supports that higher PA during pregnancy is associated with lower lipid levels throughout pregnancy with a greater effect size in women with OW/OB. Maternal lipids were associated with anthropometrics and infant body composition at two weeks of life in women with OW/OB., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Among the Oji-Cree of northern Ontario, women have both a higher prevalence and an earlier onset of type 2 diabetes compared to men. We studied the relationship between HNF1A S319 and both the presence of and the age-of-onset of type 2 diabetes in women and men separately. We found that: 1) in women, there was a significant difference in the mean age-of-onset of type 2 diabetes according to HNF1A genotype; and 2) in men, there was no difference in the mean age-of-onset of type 2 diabetes according to HNF1A genotype. The findings indicate that HNF1A S319 is associated with increased susceptibility to type 2 diabetes in both men and women, but with earlier age-of-onset in women only. One factor that might account for the gender difference in the onset of HNF1A S319-associated type 2 diabetes is the greater prevalence and severity, and earlier onset of, obesity among female Oji-Cree.

We previously showed that a rare mutation in LMNA, which encodes lamins A and C, underlies autosomal dominant Dunnigan-type familial partial lipodystrophy (FPLD). Because FPLD is an extreme example of genetically disturbed adipocyte differentiation, it is possible that common variation in LMNA is associated with obesity-related phenotypes. We therefore analyzed the relationships between the common LMNA 1908T/C single nucleotide polymorphism (SNP) and plasma leptin and anthropometric indices in 306 nondiabetic Canadian Oji-Cree. We found that subjects with the LMNA 1908T/1908T genotype had significantly higher plasma leptin than the subjects with either the 1908C/1908T or 1908C/1908C genotypes, after adjustment for age and sex. Physical indices of obesity, such as body mass index, percent body fat, and ratio of waist-to-hip circumference, were also higher among Oji-Cree subjects with the LMNA 1908T/1908T genotype than the subjects with either the 1908C/1908T or 1908C/1908C genotypes. The results suggest that common genetic variation in LMNA may be an important determinant of plasma leptin and obesity-related quantitative traits.

Background: The prevalence of pediatric obesity in North America is increasing. Native American children are at especially high risk., Objectives: The objective was to evaluate the prevalence of pediatric overweight and associated behavioral factors in a Native Canadian community with high rates of adult obesity and type 2 diabetes mellitus., Design: Height and weight were measured in 445 children and adolescents aged 2-19 y. Fitness level, television viewing, body image concepts, and dietary intake were assessed in 242 subjects aged 10-19 y. Overweight was defined as a body mass index > or =85th percentile value for age- and sex-specific reference data from the third National Health and Nutrition Examination Survey (NHANES III). Multiple logistic regression was used to examine factors associated with overweight, with adjustment for age and sex., Results: The overall prevalence of overweight in subjects aged 2-19 y was significantly higher than NHANES III reference data [boys: 27. 7% (95% CI: 21.8, 34.5); girls: 33.7% (95% CI: 27.9, 40.1)]. In the subset aged 10-19 y, > or =5 h television viewing/d was associated with a significantly higher risk of overweight than was < or =2 h/d [odds ratio (OR) = 2.52; 95% CI: 1.06, 5.98]. Subjects in the third and fourth quartiles of fitness had a substantially lower risk of overweight than did those in the first quartile [third quartile compared with first quartile: OR = 0.24 (95% CI: 0.09, 0.66); fourth quartile compared with first quartile: OR = 0.13 (95% CI: 0.03, 0. 48)]. Fiber consumption on the previous day was associated with a decreased risk of overweight (OR = 0.69; 95% CI: 0.47, 0.99 for each 0.77 g/MJ increase in fiber intake)., Conclusions: Pediatric overweight is a harbinger of future diabetes risk and indicates a need for programs targeting primary prevention of obesity in children and adolescents.

Background: In adults, the time-to-glucose-peak at or after 30 minutes during an oral glucose tolerance test (OGTT) identifies physiologically distinct groups with differences in insulin sensitivity, β-cell function and risk for type 2 diabetes. In obese non-diabetic adolescents, we investigated if the OGTT-time-to-glucose-peak also reflects incretin and free fatty acid (FFA) responses besides insulin sensitivity and β-cell function, measured by the clamp., Methods: Obese adolescents (n = 278) were categorized according to their OGTT-time-to-glucose-peak by Early-peak (at 30 minutes) vs Late-peak (>30 minutes) groups. Body composition, visceral adipose tissue, oral disposition index and OGTT-area under the curve (AUC) were examined. A subset of 102 participants had both hyperinsulinemic-euglycemic and hyperglycemic clamps to measure in vivo insulin sensitivity, insulin secretion, and β-cell function relative to insulin sensitivity., Results: Compared with the Early-peak group, the Late-peak group had impaired β-cell function relative to insulin sensitivity, lower glucose-dependent insulinotropic polypeptide-AUC, and higher FFA-AUC despite higher insulin- and C-peptide-AUC. They also had lower hepatic and peripheral insulin sensitivity despite similar percent body fat and visceral adipose tissue, and had higher prevalence of impaired glucose tolerance (all P < .05)., Conclusions: In obese non-diabetic youth, those with a Late-peak vs an Early-peak glucose during an OGTT showed diminished β-cell function, blunted incretin secretion, and lower insulin sensitivity of glucose and FFA metabolism. It remains to be determined if Late-peak glucose predicts the future development of type 2 diabetes in these high-risk youth., (© 2019 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

The glucoregulatory and hormonal responses to moderate-intensity exercise (50% VO2max for 45 min) were examined in subjects with type 2 diabetes and mild hyperglycemia. We studied seven obese subjects with type 2 diabetes and seven lean and seven obese control subjects (fasting plasma glucose levels, 7.5 +/- 0.5, 4.8 +/- 0.1, and 5.2 +/- 0.1 mmol/l, respectively). Glucose production, utilization, and cycling (flux between glucose and glucose-6-phosphate [G-6-P]) were measured with [6-(3)H]glucose and [2-(3)H]glucose using the constant specific-activity method. Insulin levels decreased normally during exercise in diabetic subjects. Plasma glucose levels decreased in diabetic subjects, but remained constant in control subjects. Basal glucose production was not different among groups and increased similarly during exercise. The decrease in plasma glucose in diabetic subjects was due to greater glucose utilization (867 +/- 83 vs. 726 +/- 143 micromol x m(-2) x min(-1); P < 0.05). This was a consequence of the mass effect of hyperglycemia, since glucose metabolic clearance increased similarly in all groups. Glucose cycling, expressed as a percentage of total glucose output (i.e., flux through G-6-P) was elevated at rest (P < 0.01), but decreased during exercise (P < 0.01). The catecholamine response to exercise was blunted in diabetic subjects, presumably indicating autonomic dysfunction. In conclusion, during moderate-intensity exercise in obese diabetic subjects with mild hyperglycemia, 1) insulin secretory responses were normally regulated; 2) glucose homeostasis was different from that in nondiabetic subjects because glucose levels decreased during exercise; 3) the decrease in plasma glucose was due to greater-than-normal rates of glucose utilization, which were sustained by hyperglycemia; and 4) elevated basal rates of glucose cycling decreased during exercise, presumably because exercise simultaneously lowered plasma glucose, was associated with a blunted catecholamine response, and accentuated an underlying defect in hepatic glucokinase activity in type 2 diabetes.

We examined the relationship between usual patterns of food intake, fattiness of food preparation and consumption, and diabetes and obesity status in a Native Canadian reserve in northwestern Ontario. Patterns of intake were estimated using a 34-item food frequency instrument. Scales and scores were developed using factor analysis procedures and were tested for reliability using coefficient alpha. Impaired glucose tolerance (IGT) and diabetes status was determined by administering a 75-g glucose tolerance test. A number of the food groups appear to have a protective effect in regard to IGT and diabetes, including vegetables [odds ratio (OR) = 0.41, confidence interval (CI) = 0.18-0.91], breakfast foods (OR = 0.41, CI = 0.18-0. 93) and hot meal foods (OR = 0.29, CI = 0.11-0.78). Most of these foods are relatively high in fiber and low in fat. High consumption of junk foods and the bread and butter group was associated with substantial increases in risk for diabetes (OR = 2.40, CI = 1.13-5. 10; OR = 2.22, CI = 1.22-4.41, respectively). These foods tend to be high in simple sugars, low in fiber and high in fat. More fatty methods of food preparation are also associated with increased risk for diabetes in this population (OR = 2.58, CI = 1.11-6.02). This information has been incorporated into an ongoing community-based diabetes prevention program in the community.

We hypothesized that genomic variation affecting the primary amino acid sequence of the intestinal fatty acid-binding protein would be related to variation in body mass index and associated clinical phenotypes in aboriginal Canadians. We studied 507 adult native Canadians from an isolated community in Northern Ontario. We found that the frequency of the T54 variant of the intestinal fatty acid-binding protein gene was 0.14 in this sample. The presence of this variant was associated with significant increases in body mass index, percent body fat, and fasting plasma triglyceride concentration (P = 0.012, 0.019, and 0.012, respectively). However, the variant was not associated with the presence of diabetes mellitus. These findings suggest that the T54 variant of the intestinal fatty acid-binding protein is associated with differences in fat metabolism in this aboriginal population.

Community-based studies of body image concepts can be useful for developing health interventions to prevent obesity-related diseases such as diabetes and cardiovascular disease in specific populations. First Nations peoples, in particular, face increased obesity-related health problems as a result of acculturative changes in diet and activity. This study examined body shape perception in an Ojibway-Cree community in Northern Ontario, Canada. A set of figure outline drawings ranging from very thin to very obese were used to examine perceived body shape, body shape satisfaction and ideals of healthiness across sex and age groups. Overall, only 16% of the population were satisfied with their current body shape. People with a higher body mass index (BMI) were less satisfied with their bodies and thought they were less healthy than people with a lower BMI. While females had a significantly greater BMI than males, males and females did not differ significantly in perception of current body shape. On the other hand, females desired relatively smaller body shapes than males (P < 0.05). Older people chose significantly larger healthy body shapes than did younger people (P < 0.05). Differences between our results and those reported for Anglo populations indicate that while both groups prefer body shapes smaller than those they have currently, the Ojibway-Cree tend to prefer relatively larger body shapes. Knowledge of age and sex-related patterns of body image concepts in communities can assist in the design of obesity-reducing interventions targeting specific groups.

Epicardial adipose tissue is a novel cardiovascular risk factor. It plays a role in the progression of coronary artery disease, heart failure and atrial fibrillation. Given its rapid metabolism, clinical measurability, and modifiability, epicardial fat works well as therapeutic target of drugs modulating the adipose tissue. Epicardial fat responds to glucagon-like peptide 1 receptor agonists (GLP1A) and sodium glucose co-transporter 2 inhibitors (SGLT2i). GLP-1A and SGLT2i provide weight loss and cardiovascular protective effects beyond diabetes control, as recently demonstrated. The potential of modulating the epicardial fat morphology and genetic profile with targeted pharmacological agents can open new avenues in the pharmacotherapy of diabetes and obesity, with particular focus on cardiovascular risk reduction., (© 2021. Italian Society of Endocrinology (SIE).)

Background: Post-stroke functional recovery is severely impaired by type 2 diabetes (T2D). This is an important clinical problem since T2D is one of the most common diseases. Because weight loss-based strategies have been shown to decrease stroke risk in people with T2D, we aimed to investigate whether diet-induced weight loss can also improve post-stroke functional recovery and identify some of the underlying mechanisms., Methods: T2D/obesity was induced by 6 months of high-fat diet (HFD). Weight loss was achieved by a short- or long-term dietary change, replacing HFD with standard diet for 2 or 4 months, respectively. Stroke was induced by middle cerebral artery occlusion and post-stroke recovery was assessed by sensorimotor tests. Mechanisms involved in neurovascular damage in the post-stroke recovery phase, i.e. neuroinflammation, impaired angiogenesis and cellular atrophy of GABAergic parvalbumin (PV)+ interneurons were assessed by immunohistochemistry/quantitative microscopy., Results: Both short- and long-term dietary change led to similar weight loss. However, only the latter enhanced functional recovery after stroke. This effect was associated with pre-stroke normalization of fasting glucose and insulin resistance, and with the reduction of T2D-induced cellular atrophy of PV+ interneurons. Moreover, stroke recovery was associated with decreased T2D-induced neuroinflammation and reduced astrocyte reactivity in the contralateral striatum., Conclusion: The global diabetes epidemic will dramatically increase the number of people in need of post-stroke treatment and care. Our results suggest that diet-induced weight loss leading to pre-stroke normalization of glucose metabolism has great potential to reduce the sequelae of stroke in the diabetic population., (© 2021. The Author(s).)

Abstract: Human obesity is associated with insulin resistance and often results in a number of metabolic abnormalities and cardiovascular complications. Over the past decades, substantial advances in the understanding of the cellular and molecular pathophysiological pathways underlying the obesity-related vascular dysfunction have facilitated better identification of several players participating in this abnormality. However, the complex interplay between the disparate mechanisms involved has not yet been fully elucidated. Moreover, in medical practice, the clinical syndromes stemming from obesity-related vascular dysfunction still carry a substantial burden of morbidity and mortality; thus, early identification and personalized clinical management seem of the essence. Here, we will initially describe the alterations of intravascular homeostatic mechanisms occurring in arteries of obese patients. Then, we will briefly enumerate those recognized causative factors of obesity-related vasodilator dysfunction, such as vascular insulin resistance, lipotoxicity, visceral adipose tissue expansion, and perivascular adipose tissue abnormalities; next, we will discuss in greater detail some emerging pathophysiological mechanisms, including skeletal muscle inflammation, signals from gut microbiome, and the role of extracellular vesicles and microRNAs. Finally, it will touch on some gaps in knowledge, as well as some current acquisitions for specific treatment regimens, such as glucagon-like peptide-1 enhancers and sodium-glucose transporter2 inhibitors, that could arrest or slow the progression of this abnormality full of unwanted consequences., Competing Interests: The authors report no conflicts of interest., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Aims/hypothesis: The aim of this study was to examine how BMI influences the association between Asian ethnicity and risk of gestational diabetes (GDM)., Methods: This population-based cohort study included pregnant women without pre-existing diabetes mellitus in Ontario, Canada between 2012 and 2014. Women of Chinese and South Asian ethnicity were identified using a validated surname algorithm. GDM was ascertained using hospitalisation codes. The relationship between ethnicity and GDM was modelled using modified Poisson regression, adjusted for maternal age, pre-pregnancy BMI, parity, previous GDM, long-term residency status, income quintile and smoking status. An interaction term between ethnicity and pre-pregnancy BMI was tested., Results: Of 231,618 pregnant women, 9289 (4.0%) were of South Asian ethnicity and 12,240 (5.3%) were of Chinese ethnicity. Relative to women from the general population, in whom prevalence of GDM was 4.3%, the adjusted RR of GDM was higher among those of South Asian ethnicity (1.81 [95% CI 1.64, 1.99]) and Chinese ethnicity (1.66 [95% CI 1.53, 1.80]). The association between GDM and Asian ethnicity remained significant across BMI categories but differed according to BMI. The prevalence of GDM exceeded 5% at an estimated BMI of 21.5 kg/m 2 among South Asian women, 23.0 kg/m 2 among Chinese women and 29.5 kg/m 2 among the general population., Conclusions/interpretation: The risk of GDM is significantly higher in South Asian and Chinese women, whose BMI is lower than that of women in the general population. Accordingly, targeted GDM prevention strategies may need to consider lower BMI cut-points for Asian populations.

Background: Overweight before pregnancy is independent risk factor for diabetes mellitus. This randomized controlled trial was to investigate the long-term effects of regular exercise during pregnancy on overweight and obese gravidas., Methods and Analysis: This single-center, prospective, randomized controlled test will be conducted in Wuhan Central Hospital, Tongji Medical College, Huazhong University of Science and Technology. Overweight and obese pregnant women will be included in our study and randomized into 2 groups: regular exercise and control groups. The informed consent will be acquired in each patient. Body weight, body fat, fasting and 2 h glucose level in 75 g oral glucose tolerance test (OGTT), insulin resistance index, and lipid profiles were compared. We also evaluated their physical activities with International Physical Activity Questionnaire (IPAQ), their dietary habits with modified Adult Dietary Behavior Assessment Scale, and depression condition with Postpartum Depression Screen Scale (PDSS). The significance level was defaulted as P < .05., Results: Results will be published in relevant peer-reviewed journals., Conclusion: Our study aims to systematically assess the effects of regular exercise for overweight and obese gravidas, which will be provided clinical guidance for overweight and obese gravidas., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2021 the Author(s). Published by Wolters Kluwer Health, Inc.)

Obesity is a global epidemic associated with over 200 health complications and a significant risk of developing cardiovascular disease (CVD), partly by increasing classical risk factors such as lipid and glucose levels and blood pressure. Weight loss through lifestyle interventions, pharmacotherapy and/or bariatric surgery improves CV risk factors. Cardiovascular outcome trials (CVOTs) of anti-obesity medications aim to evaluate the CV safety and benefits of pharmacotherapy. Many CVOTs in obesity have either failed to demonstrate a CV benefit or have been terminated prematurely because of safety issues, prompting regulatory agencies to define new requirements (based on those for CVOTs in type 2 diabetes [T2D]). CVOTs of glucagon-like peptide-1 receptor agonists (GLP-1RAs) in T2D have demonstrated that some GLP-1RAs reduce CV risk and may help inform future CVOTs in obesity, given the approval of liraglutide 3.0 mg for obesity. In this review, the evidence for the link between obesity and CVD is considered in the context of studies showing that weight loss improves markers of CV risk and risk of adverse CV events. The review also examines the CVOTs in obesity that have been conducted to date and those under way, such as the SELECT trial with subcutaneous semaglutide of 2.4 mg., (© 2020 The Authors. Obesity Reviews published by John Wiley & Sons Ltd on behalf of World Obesity Federation.)

Introduction: Obesity-associated adverse obstetric outcomes are well-known but still relatively rare and difficult to predict. Not all obese individuals are unhealthy; some have metabolically healthy obesity (MHO) and others have metabolic unhealthy obesity (MUO). Our aim was to investigate whether the MHO and MUO classification could be used for prediction of obesity-associated complications in pregnancy., Material and Methods: We included 547 pregnant women with obesity, 2302 pregnant women with overweight and 5852 normal weight pregnant women. The women with obesity were classified as MUO (n = 181, 33.1%) or MHO (n = 366, 66.9%) based on first trimester blood pressure, lipoprotein levels and nonfasting glucose levels. The risk of obstetric outcomes was evaluated by multivariable logistic regression. We compared cardiovascular risk markers in blood between obese pregnant women with MUO and MHO., Results: Overall, 45.9% of women with MUO developed at least one adverse obesity-associated obstetric outcome, whereas corresponding proportions in women with MHO, overweight and normal weight were 35.0%, 27.6% and 21.2%, respectively. Following adjustment, the overall risk of at least one obesity-associated obstetric or perinatal complication in women with MUO, vs women with MHO, was increased (adjusted odds ratio 1.49, 95% confidence interval 1.03-2.15), but the predictive value of the model was low. Women with MUO had altered levels of cardiovascular risk markers such as cathepsin S, adiponectin, and cystatin C in comparison with women with MHO., Conclusions: Women with MUO had an overall increased risk of adverse obstetric outcomes in comparison to women with MHO, but the classification had little relevance for risk prediction beyond that of body mass index., (© 2020 Nordic Federation of Societies of Obstetrics and Gynecology (NFOG). Published by John Wiley & Sons Ltd.)

Non-alcoholic fatty liver disease (NAFLD) exists as a spectrum of disease ranging from excessive accumulation of fat within the liver (simple steatosis), inflammation (non-alcoholic steatohepatitis) through to fibrosis, cirrhosis and end-stage liver disease. There is also an increased risk of hepatocellular carcinoma. The principal risk factor for NAFLD is overweight or obesity, along with type 2 diabetes, and NAFLD itself is also a risk factor for incident type 2 diabetes. Overweight/obesity is synergistic with alcohol consumption in causing progressive and insidious liver damage. Recent consensus advocates a change in nomenclature from NAFLD to 'metabolic associated fatty liver disease' (MAFLD), reflective of the associated metabolic abnormalities (insulin resistance/type 2 diabetes and metabolic syndrome components). Additional extra-hepatic manifestations of NAFLD include cardiovascular disease, chronic kidney disease and certain cancers. Unlike other micro- and macrovascular complications of type 2 diabetes, systematic screening or surveillance protocols have not been widely adopted in routine diabetes care to assess for presence/severity of NAFLD. Various screening tools are available (non-invasive tests and biochemical indices) combined with imaging techniques (e.g. transient elastography) to detect steatosis and more importantly advanced fibrosis/cirrhosis to facilitate appropriate surveillance. Liver biopsy may be sometimes necessary. Treatment options for type 2 diabetes, including lifestyle interventions (dietary change and physical activity), glucose-lowering therapies and metabolic surgery, can modulate hepatic steatosis and to a lesser extent fibrosis. Awareness of the impact of liver disease on the choice of glucose-lowering medications in individuals with type 2 diabetes is also critical., (© 2020 Diabetes UK.)

Type 2 diabetes is more common in non-Europeans and starts at a younger age and at lower BMI cut-offs. This review discusses the insights from genetic studies about pathophysiological mechanisms which determine risk of disease with a focus on the role of adiposity and body fat distribution in ethnic disparity in risk of type 2 diabetes. During the past decade, genome-wide association studies (GWAS) have identified more than 400 genetic variants associated with the risk of type 2 diabetes. The Eurocentric nature of these genetic studies has made them less effective in identifying mechanisms that make non-Europeans more susceptible to higher risk of disease. One possible mechanism suggested by epidemiological studies is the role of ethnic difference in body fat distribution. Using genetic variants associated with an ability to store extra fat in a safe place, which is subcutaneous adipose tissue, we discuss how different ethnic groups could be genetically less susceptible to type 2 diabetes by developing a more favourable fat distribution., (© 2020 The Authors. Journal of Internal Medicine published by John Wiley & Sons Ltd on behalf of Association for Publication.)