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The state of intermediate hyperglycemia is indicative of elevated risk of developing type 2 diabetes 1 . However, the current definition of prediabetes neither reflects subphenotypes of pathophysiology of type 2 diabetes nor is predictive of future metabolic trajectories. We used partitioning on variables derived from oral glucose tolerance tests, MRI-measured body fat distribution, liver fat content and genetic risk in a cohort of extensively phenotyped individuals who are at increased risk for type 2 diabetes 2 , 3 to identify six distinct clusters of subphenotypes. Three of the identified subphenotypes have increased glycemia (clusters 3, 5 and 6), but only individuals in clusters 5 and 3 have imminent diabetes risks. By contrast, those in cluster 6 have moderate risk of type 2 diabetes, but an increased risk of kidney disease and all-cause mortality. Findings were replicated in an independent cohort using simple anthropomorphic and glycemic constructs 4 . This proof-of-concept study demonstrates that pathophysiological heterogeneity exists before diagnosis of type 2 diabetes and highlights a group of individuals who have an increased risk of complications without rapid progression to overt type 2 diabetes. Clustering of patients with prediabetes using simple clinical features reveals six distinct groups with differing risk of developing type 2 diabetes and its associated complications.

Testosterone supplementation is commonly used for its effects on sexual function, bone health and body composition, yet its effects on disease outcomes are unknown. To better understand this, we identified genetic determinants of testosterone levels and related sex hormone traits in 425,097 UK Biobank study participants. Using 2,571 genome-wide significant associations, we demonstrate that the genetic determinants of testosterone levels are substantially different between sexes and that genetically higher testosterone is harmful for metabolic diseases in women but beneficial in men. For example, a genetically determined 1 s.d. higher testosterone increases the risks of type 2 diabetes (odds ratio (OR) = 1.37 (95% confidence interval (95% CI): 1.22–1.53)) and polycystic ovary syndrome (OR = 1.51 (95% CI: 1.33–1.72)) in women, but reduces type 2 diabetes risk in men (OR = 0.86 (95% CI: 0.76–0.98)). We also show adverse effects of higher testosterone on breast and endometrial cancers in women and prostate cancer in men. Our findings provide insights into the disease impacts of testosterone and highlight the importance of sex-specific genetic analyses. Genetic analysis of data from over 400,000 participants in the UK Biobank Study shows that circulating testosterone levels have sex-specific implications for cardiometabolic diseases and cancer outcomes.

Hypertension (HTN) is a major global contributor to cardiovascular morbidity and mortality. Insulin resistance is a key mechanistic factor in HTN development, yet its direct measurement is impractical in large population studies. Triglyceride–glucose (TyG) index derivatives and the Atherogenic Index of Plasma (AIP) have emerged as simple surrogate markers of metabolic dysfunction. However, limited evidence compares their associations withHTN across different glycemic statuses. This study aimed to evaluate the associations of TyG-body mass index (TyG-BMI), TyG-waist circumference (TyG-WC), TyG-waist-to-height ratio (TyG-WHtR), TyG-waist-to-hip ratio (TyG-WHR), and AIP with HTN in a large Iranian population and to determine whether these associations differ among normoglycemic, prediabetic, and diabetic subgroups. This cross-sectional analysis included 10,520 adults aged 35–70 years from the PERSIAN Guilan Cohort Study. Logistic regression models were used to estimate odds ratios (ORs) and 95% confidence intervals (CIs) for the association between each index and HTN. Discriminative performance was assessed using receiver operating characteristic (ROC) curves and area under the curve (AUC) analysis. After adjusting for confounding factors, all evaluated indices were significantly associated with HTN in the overall population. The strongest association was observed for AIP (OR = 1.66, 95% CI: 1.43–1.93; P  < 0.01), followed by TyG-WHtR (OR = 1.42, 95% CI: 1.35–1.50; P  < 0.01), TyG-WHR (OR = 1.36, 95% CI: 1.30–1.43; P  < 0.01), TyG-BMI (OR = 1.004, 95% CI: 1.004–1.005; P  < 0.01), and TyG-WC (OR = 1.002, 95% CI: 1.001–1.002; P  < 0.01). In the subgroup analysis based on glycemic status, AIP showed the strongest association among normoglycemic individuals (OR = 1.35, 95% CI: 1.10–1.67; P  < 0.01), whereas TyG-WHR demonstrated the strongest association in the prediabetic group (OR = 1.27, 95% CI: 1.12–1.46; P  < 0.01). Among individuals with diabetes, AIP again exhibited the strongest association (OR = 1.46, 95% CI: 1.09–1.97; P  = 0.01). AIP exhibited the strongest association with HTN overall and within the normoglycemic and diabetic groups, while TyG-WHR was most strongly associated with HTN among prediabetic individuals. Although all TyG-derived indices and AIP were significantly associated with HTN, their relative strengths varied by glycemic status. Using the most relevant index for each metabolic category may improve risk stratification and support more targeted prevention strategies.

The traditional complications of diabetes mellitus are well known and continue to pose a considerable burden on millions of people living with diabetes mellitus. However, advances in the management of diabetes mellitus and, consequently, longer life expectancies, have resulted in the emergence of evidence of the existence of a different set of lesser-acknowledged diabetes mellitus complications. With declining mortality from vascular disease, which once accounted for more than 50% of deaths amongst people with diabetes mellitus, cancer and dementia now comprise the leading causes of death in people with diabetes mellitus in some countries or regions. Additionally, studies have demonstrated notable links between diabetes mellitus and a broad range of comorbidities, including cognitive decline, functional disability, affective disorders, obstructive sleep apnoea and liver disease, and have refined our understanding of the association between diabetes mellitus and infection. However, no published review currently synthesizes this evidence to provide an in-depth discussion of the burden and risks of these emerging complications. This Review summarizes information from systematic reviews and major cohort studies regarding emerging complications of type 1 and type 2 diabetes mellitus to identify and quantify associations, highlight gaps and discrepancies in the evidence, and consider implications for the future management of diabetes mellitus.This article discusses evidence for the emergence of a different set of complications associated with diabetes mellitus from the traditional ones, outlines the risks and burden of these associated complications and considers implications for the future management of diabetes mellitus.

People with obesity commonly face a pervasive, resilient form of social stigma. They are often subject to discrimination in the workplace as well as in educational and healthcare settings. Research indicates that weight stigma can cause physical and psychological harm, and that affected individuals are less likely to receive adequate care. For these reasons, weight stigma damages health, undermines human and social rights, and is unacceptable in modern societies. To inform healthcare professionals, policymakers, and the public about this issue, a multidisciplinary group of international experts, including representatives of scientific organizations, reviewed available evidence on the causes and harms of weight stigma and, using a modified Delphi process, developed a joint consensus statement with recommendations to eliminate weight bias. Academic institutions, professional organizations, media, public-health authorities, and governments should encourage education about weight stigma to facilitate a new public narrative about obesity, coherent with modern scientific knowledge.

Adiponectin (APN), a protein abundantly secreted from adipocytes, has been reported to possess beneficial effects on cardiovascular diseases in association with its accumulation on target organs and cells by binding to T-cadherin. However, little is known about the role of APN in the development of diabetic microvascular complications, such as diabetic retinopathy (DR). Here we investigated the impact of APN on the progression of early retinal vascular damage using a streptozotocin (STZ)-induced diabetic mouse model. Our immunofluorescence results clearly showed T-cadherin-dependent localization of APN in the vascular endothelium of retinal arterioles, which was progressively decreased during the course of diabetes. Such reduction of retinal APN accompanied the early features of DR, represented by increased vascular permeability, and was prevented by glucose-lowering therapy with dapagliflozin, a selective sodium-glucose co-transporter 2 inhibitor. In addition, APN deficiency resulted in severe vascular permeability under relatively short-term hyperglycemia, together with a significant increase in vascular cellular adhesion molecule-1 (VCAM-1) and a reduction in claudin-5 in the retinal endothelium. The present study demonstrated a possible protective role of APN against the development of DR.

Currently, type 2 diabetes mellitus (T2DM) and obesity are major global public health issues, and their prevalence in the United Arab Emirates (UAE) are among the highest in the world. In 2019, The UAE diabetes national prevalence was 15.4%. In recent years there has been a considerable investigation of predictive biomarkers associated with these conditions. This study analysed fasting (8 h) blood samples from an obese, normoglycemic cohort and an obese, T2DM cohort of UAE nationals, employing clinical chemistry analysis, 1D 1 H NMR and mass spectroscopy (FIA-MS/MS and LC-MS/MS) techniques. The novel findings reported for the first time in a UAE population revealed significant differences in a number of metabolites in the T2DM cohort. Metabolic fingerprints identified by NMR included BCAAs, trimethylamine N-oxide, β-hydroxybutyrate, trimethyl uric acid, and alanine. A targeted MS approach showed significant differences in lysophosphatidylcholines, phosphatidylcholines, acylcarnitine, amino acids and sphingomyelins; Lyso.PC.a.C18.0, PC.ae.C34.2, C3.DC..C4.OH, glutamine and SM.C16.1, being the most significant metabolites. Pearson’s correlation studies showed associations between these metabolites and the clinical chemistry parameters across both cohorts. This report identified differences in metabolites in response to T2DM in agreement with many published population studies. This contributes to the global search for a bank of metabolite biomarkers that can predict the advent of T2DM and give insight to its pathogenic mechanisms.

Type 2 diabetes is characterized by insulin resistance and a gradual loss of pancreatic beta cell mass and function 1 , 2 . Currently, there are no therapies proven to prevent beta cell loss and some, namely insulin secretagogues, have been linked to accelerated beta cell failure, thereby limiting their use in type 2 diabetes 3 , 4 . The adipokine adipsin/complement factor D controls the alternative complement pathway and generation of complement component C3a, which acts to augment beta cell insulin secretion 5 . In contrast to other insulin secretagogues, we show that chronic replenishment of adipsin in diabetic db / db mice ameliorates hyperglycemia and increases insulin levels while preserving beta cells by blocking dedifferentiation and death. Mechanistically, we find that adipsin/C3a decreases the phosphatase Dusp26 ; forced expression of Dusp26 in beta cells decreases expression of core beta cell identity genes and sensitizes to cell death. In contrast, pharmacological inhibition of DUSP26 improves hyperglycemia in diabetic mice and protects human islet cells from cell death. Pertaining to human health, we show that higher concentrations of circulating adipsin are associated with a significantly lower risk of developing future diabetes among middle-aged adults after adjusting for body mass index (BMI). Collectively, these data suggest that adipsin/C3a and DUSP26-directed therapies may represent a novel approach to achieve beta cell health to treat and prevent type 2 diabetes. Targeting the adipokine adipsin and its downstream pathway may provide an approach for preservation of beta cell loss in type 2 diabetes.

Polycystic ovary syndrome (PCOS) is a heterogeneous familial disorder affecting up to one in five women. The aetiology remains unclear, but available evidence suggests it is a polygenic disorder with epigenetic, developmental, and environmental components. The diagnostic criteria for PCOS are based on reproductive features, and the syndrome is categorized into several phenotypes that can vary by race and ethnicity. Insulin resistance and metabolic dysfunction have a crucial role in the pathogenesis of the syndrome and contribute to many adverse metabolic outcomes that place a substantial burden on the health of women with PCOS across their lifespan. Metabolic abnormalities like those identified in women with PCOS are also present in their female and male first-degree relatives. Overall, more emphasis is required on defining PCOS as a metabolic disorder in addition to a reproductive one. This approach could affect the management and future treatment options for the syndrome. The rationale of the current review is to identify and analyse existing evidence for PCOS as a metabolic, as well as a reproductive, disease. Polycystic ovary syndrome (PCOS) is characterized not only by reproductive symptoms and hyperandrogenism but also by metabolic abnormalities, such as insulin resistance and obesity. This Review discusses the evidence of metabolic disorders in PCOS and for understanding PCOS as a metabolic disease. Key points Beyond reproductive features, polycystic ovary syndrome (PCOS) is associated with an increased prevalence of several metabolic abnormalities, some of which are also observed in the first-degree relatives of women with PCOS. Insulin resistance and compensatory hyperinsulinaemia, intrinsic to PCOS and exacerbated by obesity, are major drivers of metabolic complications and strong determinants of reproductive dysfunction and hyperandrogenaemia in affected women. The clinical presentation of PCOS is heterogeneous and can be categorized into several phenotypes that can vary by life stage, race and/or ethnicity and degree of adiposity. Cluster analysis suggests that there are reproducible reproductive and metabolic PCOS subtypes with distinct genetic architecture, which cannot be identified by the current diagnostic criteria. With advances in omics-based studies and artificial intelligence-based methods, it might be possible to classify women with PCOS into subgroups that correlate with the clinical severity and identify those at high risk of long-term metabolic complications.

Key Points Short-chain fatty acids (SCFA), which are derived from gut microbial fermentation of indigestible foods, have important metabolic functions and are crucial for intestinal health The discovery of SCFA receptors in many different tissues highlights that SCFA are involved in the crosstalk between the gut and peripheral tissues In addition to their role in gut health and as signalling molecules, SCFA might enter the systemic circulation and directly affect substrate metabolism and function of peripheral tissues SCFA might increase intestinal energy harvesting and promote the development of obesity, but could also increase energy expenditure and anorexic hormone production, as well as improving appetite regulation Increasing evidence supports a beneficial role for SCFA in adipose tissue, skeletal muscle and liver substrate metabolism and function, thereby contributing to improved insulin sensitivity Well-controlled human intervention studies investigating the role of SCFA and differential SCFA availability on gut and systemic metabolic health are eagerly awaited Short-chain fatty acids (SCFA) are produced by the gut microbiota from indigestible food stuffs, and might have beneficial effects on metabolism and insulin sensitivity. Here, Canfora and colleagues discuss how SCFA can modulate energy homeostasis and metabolism in adipose tissue, muscle and the liver. The authors also discuss whether SCFA might be used to modulate glucose homeostasis in humans. The connection between the gut microbiota and the aetiology of obesity and cardiometabolic disorders is increasingly being recognized by clinicians. Our gut microbiota might affect the cardiometabolic phenotype by fermenting indigestible dietary components and thereby producing short-chain fatty acids (SCFA). These SCFA are not only of importance in gut health and as signalling molecules, but might also enter the systemic circulation and directly affect metabolism or the function of peripheral tissues. In this Review, we discuss the effects of three SCFA (acetate, propionate and butyrate) on energy homeostasis and metabolism, as well as how these SCFA can beneficially modulate adipose tissue, skeletal muscle and liver tissue function. As a result, these SCFA contribute to improved glucose homeostasis and insulin sensitivity. Furthermore, we also summarize the increasing evidence for a potential role of SCFA as metabolic targets to prevent and counteract obesity and its associated disorders in glucose metabolism and insulin resistance. However, most data are derived from animal and in vitro studies, and consequently the importance of SCFA and differential SCFA availability in human energy and substrate metabolism remains to be fully established. Well-controlled human intervention studies investigating the role of SCFA on cardiometabolic health are, therefore, eagerly awaited.