Metabolic dysfunction-associated steatotic liver disease (MASLD), formerly called non-alcoholic fatty liver disease (NAFLD), is today the leading cause of chronic liver conditions in the context of a global epidemic of obesity and metabolic disorders. Our study aims to determine the prevalence of MASLD and advanced liver fibrosis as well as the associated factors in patients with type 2 diabetes Mellitus (T2D). Cross-sectional study including 149 patients with T2D, conducted in the Endocrinology-Diabetology and Hepato-Gastroenterology departments over a period of 6 months. Screening for steatosis and liver fibrosis was carried out using FibroScan. The average age of the patients was 57.9 ± 11.8 years, with a female predominance (63.8%). Based on the EASL cutoffs, the MASLD ratio was 69.1% [95% CI (61.7-76.5], n = 103). Multivariable analysis identified high Body Mass Index [aOR = 1.25; 95% CI (1.13-1.38); p < 0.001] and total cholesterol [aOR = 1.69; 95% CI (1.15-2.48); p = 0.007] as independent predictors of MASLD. The median liver stiffness measurement was 5.0 kPa (IQR 4.0-6.5). Advanced fibrosis was confidently ruled out (< 8 kPa) in 82.6% (n = 123) of patients. Advanced fibrosis could not be ruled out (≥8 kPa) in 17.4% [95% CI (11.7-24.5), n = 26], which included 13.4% (n = 20) in the intermediate-risk zone (8-11.99 kPa) and 4% (n = 6) at high risk of advanced fibrosis (≥12 kPa). Higher platelet distribution width (PDW) was associated with nearly a threefold increase in the odds of advanced fibrosis (aOR = 2.78; 95% CI: 1.08-7.21; p = 0.035), while increasing GGT levels were also significantly associated with advanced fibrosis (aOR = 1.12; 95% CI: 1.03-1.21; p = 0.006). In our study, we found that 69.1% of participants met the criteria for MASLD, and advanced fibrosis could not be ruled out in 17.4% of patients, with 4% being at high risk (≥12 kPa). It is essential to identify these at-risk patients who require multidisciplinary management in order to prevent progression to cirrhosis and its complications.
Background: Gestational diabetes mellitus (GDM) and polycystic ovary syndrome (PCOS) are clinically distinct disorders that share important metabolic features. This Perspective proposes a non-causal intergenerational framework linking maternal PCOS-related metabolic vulnerability, susceptibility to GDM, intrauterine metabolic exposure, and later reproductive-metabolic risk in female offspring. Methods: A narrative synthesis of evidence from reproductive endocrinology, obstetrics, diabetology, developmental biology, and public health was undertaken. The strength of evidence supporting individual components of the proposed continuum was qualitatively appraised. Separately, aggregated surveillance data from Belgrade for 2015-2024 were used as a registry-based illustration of ICD-10 O24.4-coded GDM diagnoses. No formal time-series analysis, causal modeling, or forecasting was performed. Results: Evidence was strongest for the increased risk of GDM among women with PCOS and for the association between intrauterine exposure to maternal diabetes and later offspring metabolic susceptibility. Evidence linking maternal PCOS with offspring metabolic vulnerability was less definitive, while direct evidence that GDM exposure leads to clinically diagnosed PCOS in female offspring remained weak and indirect. Registry-recorded GDM rates varied across years, but this variability may reflect differences in screening, diagnostic criteria, coding, reporting completeness, and healthcare access rather than true changes in prevalence. Conclusions: The proposed GDM-PCOS continuum is a hypothesis-generating and probabilistic framework, not an established causal pathway. Its clinical value lies in connecting prevention opportunities before conception, during pregnancy, after delivery, and across the life course. Longitudinal maternal-offspring studies are required to test the proposed relationships.
Health literacy (HL) is a key determinant of diabetes self-management and clinical outcomes in type 2 diabetes mellitus (T2DM). The Diabetes Health Literacy Scale (DHLS) is a 14-item instrument assessing informational, numeracy, and communicative HL, with established validity in Korean, Persian, Malay, and Chinese populations. This study aimed to translate and culturally adapt the DHLS into Italian and evaluate its structural validity, internal consistency, construct validity, and measurement invariance across Italian-born and foreign-born adults with T2DM. A total of 300 adults with T2DM were recruited from two outpatient diabetology clinics in Florence, Italy. DHLS translation followed ISPOR guidelines with cognitive debriefing. Psychometric evaluation followed COSMIN recommendations and included confirmatory factor analysis, McDonald's omega, Pearson's correlations with comparator instruments, and multigroup confirmatory factor analysis (CFA). CFA supported the three-factor second-order structure (CFI = 0.921, RMSEA = 0.077). Internal consistency was satisfactory across domains (ω = 0.759-0.868) and excellent for the total scale (ω = 0.940; ωH = 0.770). All convergent validity hypotheses were supported. Multigroup CFA demonstrated configural but only partial metric invariance across birthplace groups. The DHLS-IT is a valid and reliable instrument for assessing diabetes HL in Italian adults with T2DM. Partial metric invariance cautions against direct latent score comparisons between Italian-born and foreign-born patients.
暂无摘要（点击查看详情）
The management of type 2 diabetes (T2D) has recently witnessed a paradigm shift extending beyond blood glucose regulation towards cardiovascular and renal health targeted by cardiovascular outcome trials (CVOTs) of glucagon-like peptide-1 receptor agonists (GLP-1RAs) and sodium-glucose cotransporter-2 inhibitors (SGLT2i). Preclinical studies suggest a potential role for GLP-1RAs and SGLT2i in the treatment of diabetic neuropathy and neuropathic pain. However, to date largely only small-size phase II shorter-term randomized controlled trials (RCTs) of heterogeneous designs and quality have been performed, without clear evidence of favorable effect of both GLP-1RAs and SGLT2i on clinical and neurophysiological neuropathic outcomes. Moreover, responses to GLP1-RA and SGLT2i treatments in real‑world clinical practice appear heterogeneous, with relatively high rates of non-responders and discontinuation. Several possible risks associated with GLP-1RAs and SGLT2i treatment in real-world practice have been identified requiring increased attention by physicians, their professional societies, and patients alike. Unfortunately, the opportunity has been missed to use simple tools for the detection and monitoring of diabetic sensorimotor polyneuropathy (DSPN) and cardiovascular autonomic neuropathy (CAN) in the multiple published large-scale pivotal CVOTs. Diabetic neuropathy is linked to considerable patient burden and mortality, and there remains an unmet need for the disease modifying effects of novel pharmacotherapies derived from the pathogenetic concepts of diabetic neuropathy. In the future, when designing and conducting RCTs more emphasis should be placed on considering neuropathy as a serious and potentially life-threatening complication.
Recent awareness that metabolic dysfunction-associated steatotic liver disease (MASLD) is a common liver condition in individuals with type 2 diabetes and carries a significant risk of cirrhosis and extrahepatic disease has called for an examination of its relationship with diabetes-related complications. MASLD, especially at-risk steatohepatitis (metabolic dysfunction-associated steatohepatitis [MASH]) with significant fibrosis ≥F2, shares many metabolic abnormalities with type 2 diabetes, including insulin resistance, gluco- and lipotoxicity, chronic subclinical inflammation and mitochondrial impairment. In addition, many cross-sectional and longitudinal observational studies suggest an association between MASLD and micro- and macrovascular complications of type 1 and type 2 diabetes. However, a causal pathogenic relationship has been difficult to confirm given the overlap of cardiometabolic risk factors (CMRFs) in MASLD and type 2 diabetes. Complicating matters further, most of the available evidence has significant limitations. These include shortcomings in participant selection, heterogeneity in study design, use of diagnostic tools with low sensitivity for liver disease and diabetes-related complications, inadequate control for alcohol consumption or CMRFs, and lack of repeat measurements during longitudinal studies. Nevertheless, current evidence suggests that MASLD is a 'risk enhancer' for both micro- and macrovascular disease in diabetes, rather than an independent risk factor. Here, we review the underlying mechanistic pathways and clinical evidence that appear to link both conditions and identify knowledge gaps in need of future research. Until more robust evidence emerges, we hope that a greater awareness about the link between MASLD and diabetes-related micro- and macrovascular complications will prompt clinicians to educate their patients and peers on the potentially heightened health risks of MASLD and encourage clinicians to take a more proactive approach to risk stratification and intervention.
Sarcopenia is a major contributor to frailty and mortality in ageing and obesity and is tightly linked to metabolic dysfunction. Imeglimin is a first-in-class oral hypoglycaemic agent targeting mitochondrial function; however, despite the central role of mitochondria in skeletal muscle homeostasis, its effects on skeletal muscle under sarcopenia-relevant conditions remain unclear. Imeglimin was administered to male C57BL/6 mice with high-fat diet (HFD)-induced obesity for 6 weeks and to naturally aged (18 months old) male mice for 12 weeks. Skeletal muscle fibre morphology and transcriptomic profiles were analysed in fast- and slow-twitch muscles. In parallel, C2C12 myotubes were exposed to palmitate with or without imeglimin, and inflammatory gene expression and reactive oxygen species (ROS) generation were assessed. Imeglimin significantly increased the cross-sectional area (CSA) of Type II fibres in the extensor digitorum longus (EDL) muscle of HFD-fed mice (+66%, p < 0.01 vs. controls). Transcriptomic analyses revealed suppression of conserved molecular signatures of muscle atrophy, including activation of immediate-early genes and inflammatory pathways (-62% to -79%, p < 0.05 vs. HFD-fed mice). In palmitate-treated C2C12 myotubes, imeglimin attenuated lipotoxicity-induced inflammatory gene expression (-28% to -72%, p < 0.05 vs. controls) with reduced ROS generation, consistent with its cell-autonomous effect on myocytes. Notably, in naturally aged mice, 12-week imeglimin treatment preserved EDL muscle fibre size (+14%, p < 0.05 vs. controls) without altering systemic glucose tolerance, accompanied by transcriptomic changes overlapping with those observed in the HFD model (-27% to -82%, p < 0.05 vs. aged controls). Imeglimin attenuates skeletal muscle atrophy in obesity and ageing, accompanied by coordinated suppression of stress- and inflammation-associated transcriptional programmes. These findings indicate that pharmacological regulation of mitochondrial stress responses influences skeletal muscle vulnerability under chronic metabolic stress and identify skeletal muscle as a previously underappreciated target of imeglimin action.
Cystic fibrosis-related diabetes (CFRD) is a common comorbidity in cystic fibrosis (CF), significantly impacting morbidity and mortality. Recent advancements in therapy and diabetes technology have transformed the management of CF and diabetes. This study aims to assess the evolution of CFRD and its treatment over the past few decades in a large cohort receiving routine care. Longitudinal data of 1039 persons with CFRD (median age at CFRD onset (Q1;Q3): 15.7 (13.2-19.9) years; 57.2% females) from the Diabetes Prospective Follow-up (DPV) database between 2000 and 2023 were analyzed. Changes in demographics, anthropometrics and diabetes therapy were studied using adjusted linear and logistic regression models. BMI-SDS at CFRD diagnosis increased from -0.62 (-1.78;+0.12) in 2000 to -0.45 (-0.81; +0.36) in 2023 (p = 0.002), while age at CFRD diagnosis decreased from 14.8 (13.4;19.1) years in 2000 to 12.5 (11.3;14.7) years in 2023 (p = 0.033). Pharmacological CFRD treatment has changed over the past years. Insulin monotherapy increased from 65.1% to 78.7% (p = 0.044), while OAD/GLP-1 RA-only use decreased (16.9% to 0.7%, p < 0.001). Insulin pump therapy was documented in 26.2% of people with CFRD (PwCFRD) in 2023. The use of CGM increased continuously since 2015, with 76.7% of participants using CGM in 2023 (p < 0.001). Proportion with underweight dropped from 34.3% in 2000 to 14.2% in 2023 (p < 0.001), while overweight increased during this period from 1.5% to 6% (p = 0.011). Insulin monotherapy and in particular diabetes technology is used more frequently. Improvements in CF therapy are reflected in increasing BMI-SDS and a decrease in the proportion of underweight people with CFRD.
Mushroom poisoning caused by Amanita phalloides, primarily mediated by the toxin α-amanitin (AMA), frequently leads to fatal liver failure, yet no specific antidote is currently available. Although AMA is known to inhibit RNA polymerase II, its complete cytotoxic mechanism remains unclear. This study aimed to repurpose the antifungal drug posaconazole as a first-in-class antidote targeting the host glycosylation machinery to mitigate AMA-induced liver injury. Posaconazole was identified through STT3B-focused virtual screening followed by in vitro cell-based screening. Its protective effects were evaluated in 2D and 3D cell cultures via microscopy, cell viability assays and Calcein-AM/PI staining. Therapeutic efficacy in vivo was assessed in a lethal mouse model by serum biochemical analysis, H&E, immunohistochemistry, and survival analysis. The interactions between posaconazole and STT3B was examined by molecular docking and an endoplasmic reticulum-localized luciferase reporter assay. N-glycosylation level was analyzed by lectin staining. ST6GAL1 was knockdown by shRNA. The concentrations of AMA were quantified by high-performance liquid chromatography. Posaconazole robustly protected human hepatocytes from AMA-induced toxicity in both 2D and 3D cultures. In a lethal mouse model, post-exposure treatment with posaconazole significantly attenuated AMA-induced liver injury and improves survival, achieving efficacy comparable to prior candidate. Mechanistically, posaconazole potentially inhibited the STT3B-mediated N-glycosylation, thereby suppressing down-stream sialylation. The genetic ablation of sialyltransferase ST6GAL1 confirmed that reduced sialylation limits cellular AMA uptake and confers resistance to toxicity. Our work unveils a critical glycosylation-dependent pathway for AMA toxicity and nominates posaconazole as a clinically translatable, host-directed therapeutic candidate for the treatment of lethal Amanita phalloides poisoning.
[This corrects the article DOI: 10.1016/j.lanepe.2026.101715.].
The global burden of diabetes mellitus and its chronic complications-including premature atherosclerotic cardiovascular disease and microvascular impairments such as nephropathy, retinopathy, and neuropathy-highlights the need for improved strategies for the early identification of individuals at risk of carbohydrate metabolism disorders. Growing evidence suggests that alterations in the microcirculatory bed occur concomitantly with, or may even precede, the development of cardiovascular disease. The eye, owing to its transparent anatomical structures, provides a unique opportunity for the in vivo assessment of microvascular changes and offers valuable insights into other vascular territories, serving as a potential "window" into cardiometabolic disorders. Recent advances in microcirculation imaging have enabled detailed, non-invasive evaluation of the retinal microvasculature. Techniques such as scanning laser Doppler flowmetry (SLDF), adaptive optics (AO), optical coherence tomography angiography (OCTA), and laser speckle flowgraphy (LSFG) allow for quantitative assessment of the retinal microvascular bed, demonstrating partial correlation with invasive measures of vascular function and sensitivity to therapeutic interventions. The integration of these imaging modalities into clinical and research settings may facilitate the early detection of microvascular dysfunction, improve risk stratification, and support the monitoring of disease progression and treatment efficacy in patients with carbohydrate metabolism disorders. Therefore, this review aims to summarize the current evidence on retinal microvascular alterations in carbohydrate metabolism disorders assessed using advanced imaging techniques, focusing primarily on early, subclinical retinal changes that precede the onset of diabetic retinopathy.
Continuous glucose monitoring (CGM) interpretation in people without diabetes is expanding beyond general glycemic control toward more dynamic metrics, such as Rate of Change (RoC). In this fixed-sequence pilot study conducted in 30 healthy adult females, we evaluated associations between two structured 14-day lifestyle interventions and free-living conditions using standard CGM-derived glycemic variability metrics and a novel framework based on the rate-of-change (RoC) metrics and data clarity using an unblinded Abbott FreeStyle Libre 2 monitoring. The dietary intervention (calorie-tailored low-glycemic index regular meals) were associated with lower time spent in rising (+1 to +2 mg/dL/min) and falling (-2 to -1 mg/dL/min) RoC bins by 4.76 ± 1.87% (complete-case delta, p ≤ 0.0071), whereas the 14-day physical activity intervention showed smaller and less consistent RoC changes (0.41 ± 2.20, p ≥ 0.3549). These findings, despite some major study design limitations, suggest that RoC may be more responsive and sensitive to short-term dietary pattern modifications in normoglycemic women.
This study aimed to evaluate whether the 'Okomarigoto Sheet' (OS), an illustration-based tool for patients with rheumatoid arthritis (RA), correlates with conventional measures and elicits patient symptoms. The OS includes 3 symptom scales: morning stiffness duration, and visual analogue scale (VAS) for joint pain and VAS for fatigue. Five illustrations depicting 5 different situations for each symptom were also scored (0 = none, 1 = present, and 2 = severe, respectively). Patients with RA were recruited from 4 Japanese clinics. Correlations between the OS and conventional RA-related measures were assessed using Spearman's rank correlation. Eighty patients with RA participated in this study. The total score of all 15 illustrations positively correlated with the Disease Activity Score using the Clinical Disease Activity Index and negatively with the physical and mental component scores of the Short-Form-12. Stiffness duration, pain VAS, and fatigue VAS were each positively correlated with the respective total of 5 illustrations. Among patients scoring 0 on stiffness duration, pain VAS, or fatigue VAS, a total of 10 patients showed symptoms in the corresponding illustrations. Patient global assessment (PGA) was correlated with the total score of 5 illustrations for each of the 3 symptoms, whereas evaluator global assessment (EGA) correlated only with those for stiffness and pain, not fatigue. The OS reflected standard measures of disease activity and quality of life. It also has the potential to clarify symptoms that are not captured by conventional measures. Furthermore, the OS suggested that fatigue may be one of the factors contributing to the discrepancy between PGA and EGA.
Distinguishing Graves' disease (GD) from the other causes of thyrotoxicosis is essential for appropriate management. The clinical phenotype of GD has evolved over time and is currently more heterogenous and milder than in the past. Consequently, the differential diagnosis of thyrotoxicosis is often challenging. We aim to provide clinicians with a practical guide to achieve a more reliable etiological diagnosis of thyrotoxicosis. We reviewed international guidelines and the main papers indexed in PubMed from inception to March 1, 2026, on the diagnosis of thyrotoxicosis. Three major diagnostic tools are currently available: thyroid scintigraphy, thyrotropin receptor antibodies (TRAbs), and thyroid ultrasonography (US). The diagnostic accuracy of scintigraphy is approximately 96%. However, GD may also present with non-uniform or normal uptake in 5-12% of cases. The diagnostic accuracy of TRAbs is approximately 95%. Nevertheless, TRAbs have limited utility in three specific settings: TRAb-negative GD, TRAb positivity in non-GD patients, and type 1 amiodarone-induced thyrotoxicosis (AIT). Thyroid US is the third most accurate diagnostic tool, with an accuracy of approximately 77%. Minor diagnostic tools include: T3/T4 and fT3/fT4 ratios; fT3/TSH and fT4/TSH ratios; serum diiodotyrosine; blood cell line ratios; and selected extrathyroidal manifestations of GD, such as neutropenia, abnormal liver function tests, and thymic hyperplasia. One or more major diagnostic tools may be used to establish the final etiological diagnosis of thyrotoxicosis, depending on test availability, turnaround time, and clinician expertise. Minor diagnostic tools may provide additional diagnostic information in selected or equivocal cases.
To assess the effect of all the approved classes of medications for type 2 diabetes on Major Adverse Cardiovascular events (MACE) and all-cause mortality. We performed a pairwise and network meta-analysis, including randomised controlled trials with a duration of at least 40 weeks, comparing medications versus placebo or an active comparator, in which MACE and deaths were adjudicated. We included 93 studies. In pairwise meta-analyses, versus all comparators, GLP-1 receptor agonists (GLP1RA), SGLT-2 inhibitors (SGLT2i), metformin and pioglitazone were associated with a significant reduction of MACE and sulfonylureas with increased MACE. Furthermore, tirzepatide, SGLT2i and GLP1RA were associated with a significantly reduced all-cause mortality. In the principal (frequentist) network meta-analysis, metformin (OR 0.69, 95% CI 0.53-0.89), SGLT2i (0.82, 0.75-0.90), GLP1RA (0.87, 0.83-0.92) and tirzepatide (0.82, 0.72-0.93) were associated with a significant reduction of MACE versus placebo; no effect was observed for insulin, DPP4 inhibitors (DPP4i) or sulfonylureas. Tirzepatide (0.72, 0.64-0.82), SGLT2i (0.85, 0.80-0.91) and GLP1RA (0.85, 0.80-0.91) were associated with a significantly reduced mortality versus placebo; no effect was detected for other drugs. The sensitivity (Bayesian) analysis did not confirm the significance of results for pioglitazone on MACE. The certainty of evidence was moderate-to-high for GLP1RA, SGLT2i, Tirzepatide, DPP4i; low for metformin; low-to-moderate for other drugs. SGLT2i, GLP1RA, tirzepatide and (with lower quality of evidence) pioglitazone and metformin are associated with a reduced incidence of cardiovascular events; tirzepatide, SGLT2i and GLP1RA are also associated with a reduced all-cause mortality.
Hypertension is one of the main modifiable risk factors for ischemic stroke related to large artery atherosclerosis. Arterial stiffness indices may improve risk stratification beyond blood pressure (BP) measurement alone. Increased pulse wave velocity (PWV) is a risk and prognostic factor for ischemic stroke (IS) and is associated with carotid artery atherosclerosis. We investigated whether the aortic-brachial pulse wave velocity (PWV) ratio differs between stroke subtypes and whether it is independent of mean blood pressure (MBP) in ischemic stroke patients. We measured carotid-radial (cr-PWV) and carotid-femoral PWV (cf-PWV) on day 6 of hospitalization in 188 IS subjects. PWV ratio was calculated as cf-PWV/cr-PWV. The etiology of stroke was determined following appropriate diagnostic investigations. Stroke etiology was determined according to TOAST classification. Associations between PWV ratio, stroke subtype, and MBP were analyzed using uni- and multivariate models. Forty-one patients (21.8%) had stroke related to large artery atherosclerosis (LAA). The PWV ratio was higher in LAA compared with non-LAA stroke [1.26 (1.09-1.58) vs. 1.10 (0.95-1.36), p < 0.01], remaining significant after adjustment (OR = 3.40, 95%CI = 1.18-9.79, p = 0.02). PWV ratio was not associated with MBP (p = 0.79). PWV ratio is elevated in LAA-related ischemic stroke and was not significantly associated with BP, supporting its potential role as a vascular risk marker.
Bacillus Calmette-Guérin (BCG) is the only vaccine for tuberculosis (TB) and remains the most effective means of prevention; however, its effectiveness in humans is highly variable with unknown mechanism. Using microbiota transplantation and multi-omics strategies (16S rRNA sequencing, metabolomics, proteomics) in mouse models, we investigated the effect of pre-vaccination gut microbiota composition on BCG vaccine efficacy. Furthermore, key findings were validated in human datasets. Baseline abundance of gut microbiota, especially Akkermansia muciniphila, significantly affects BCG vaccine efficacy. Increasing the baseline levels of A. muciniphila in the gut before vaccination reduced the BCG vaccine responses, resulting in impaired protection against Mycobacterium tuberculosis (Mtb) infection in mice. A. muciniphila-contributed gut co-metabolite palmitoleic acid inhibits the vaccine responses of BCG. Palmitoleic acid acts on vaccine response through the mediation of effector protein MptpB of BCG and identified that MptpB-mediated inhibition of actin cytoskeleton remodelling to activate BCG vaccine responses is required for palmitoleic acid to regulate the efficacy of BCG vaccination. Inhibition of MptpB or actin cytoskeleton remodelling blocks the effects of higher baseline abundance of A. muciniphila on the efficacy of BCG vaccination. Analyses of human datasets provided hypothesis-generating support for these findings. Mechanistically, the higher baseline levels of gut A. muciniphila and its metabolite palmitoleic acid inhibit BCG vaccine efficacy by suppressing MptpB-mediated actin cytoskeleton remodelling. These results show that pre-vaccination differences in gut microbiota composition are a factor accounting for high variation in vaccine effectiveness. Stratifying by baseline gut microbiota profile and metabolism may represent a strategy to enhance future vaccine efficacy. Guang Dong Cheung Kong Philanthropy Foundation, Guangzhou key R & D project, National Natural Science Foundation of China, Key laboratory start-up project (Sixth Affiliated Hospital of Sun Yat-sen University), Guangdong Basic and Applied Basic Research Foundation, Guangzhou Basic and Applied Basic Research Foundation, Doctoral Initial Funding of Guangdong Medical University, Shenzhen Medical Research Fund, Discipline construction project of Guangdong Medical University, Project of Songshan Lake Innovation Center of Medicine & Engineering of Guangdong Medical University.
暂无摘要（点击查看详情）
Environmental exposures have been adversely associated with the risk of diabetes but their role in the remission and progression of prediabetes (impaired glucose tolerance [IGT] and/or impaired fasting glucose [IFG]), especially different phenotypes, is poorly understood. This study aimed to investigate the relationship between environmental exposures and remission or progression of prediabetes phenotypes. Data were derived from the KORA (Cooperative Health Research in the Region of Augsburg) cohort in Southern Germany (2006-2022). Glucose tolerance status was defined according to the 1999/2006 WHO criteria. We included annual values of particulate matter (PM), light at night (LAN), normalised difference vegetation index (NDVI), imperviousness (IMP) and air temperature variation (Tsd). We fitted complementary log-log regression models for associations between IQR changes in exposures and the incidence of prediabetes phenotypes (isolated impaired fasting glucose [iIFG], isolated impaired glucose tolerance [iIGT], or their combination [IFG+IGT]), remission to normal glucose tolerance (NGT) or progression to type 2 diabetes. We also applied Quantile g-computation regression models for joint association analysis. During the follow-up, 370/1618 participants developed prediabetes (124 iIFG, 199 iIGT and 47 IFG+IGT). Among participants with prediabetes, 136/367 (without medication) regressed to NGT and 133/420 progressed to type 2 diabetes. We observed consistent associations of air pollutants and the built environment with iIGT or IFG+IGT. For example, an IQR increase in PM2.5 (aerodynamic diameter ≤2.5 μm) showed an HR of 1.89 (95% CI 1.07, 3.31) for the risk of IFG+IGT and 1.59 (95% CI 1.03, 2.46) with a decrease in NDVI. Co-exposure to environmental mixtures (higher air pollution, Tsd, IMP and LAN, and lower NDVI) was associated with increased risks of iIFG, iIGT and IFG+IGT. Additionally, lower NDVI (HR 0.52 [95% CI 0.28, 0.96]), higher LAN (HR 0.22 [95% CI 0.08, 0.62]) and higher IMP were associated with reduced remission of iIFG but we found no statistically significant associations with the progression to type 2 diabetes. The findings indicate potential heterogeneity in environmental exposures and prediabetes phenotypes. Specifically, they are associated with increased incidence of IGT and decreased remission of iIFG.
Growing interest in precision diagnostics has stimulated efforts to classify type 2 diabetes into more granular subtypes. Recent research has focused on four pathophysiology-based subtypes: severe insulin-deficient diabetes (SIDD); severe insulin-resistant diabetes (SIRD); moderate obesity-related diabetes (MOD); and moderate age-related diabetes (MARD). While these subtypes provide an attractive framework for precision medicine, they also come with methodological challenges. This narrative review highlights three key issues: (1) uncertainty about the existence of four discrete subtypes; (2) low certainty in subtype assignment; and (3) limited evidence for prognostic and therapeutic value compared with other approaches. As an alternative to subtyping, we discuss individualised prediction models, which provide personalised treatment recommendations based on routine clinical features. These models avoid some of the limitations of discrete subtyping but they do not provide insights into a person's underlying pathophysiology. Thus, these two approaches can be viewed as complementary, each serving a different purpose in precision medicine.