This study evaluated the use of transient elastography (TE) to assess the severity of metabolic dysfunction-associated steatotic liver disease (MASLD), formerly known as non-alcoholic fatty liver disease (NAFLD), in patients with type 2 diabetes mellitus (T2DM), with the aim of exploring the cross-sectional association between hepatic steatosis and prevalent coronary heart disease (CHD) in this population. A total of 104 patients with T2DM were included. TE measurements were obtained using FibroScan® (Paris, France) to determine liver stiffness values, reflecting the degree of hepatic fibrosis, and the controlled attenuation parameter (CAP), which quantifies hepatic steatosis. The presence of CHD was evaluated by coronary computed tomography angiography (CTA), with invasive coronary angiography reserved for definitive confirmation in cases with CTA findings suggestive of significant stenosis. Statistical analyses comprised univariate and multivariate logistic regression models, along with receiver operating characteristic (ROC) curve analysis. The events-per-variable ratio was approximately 10. Internal validation was performed using 1,000-fold bootstrap resampling. Based on coronary CTA findings, patients were categorized into a CHD group (n = 50) and a non-CHD group (n = 54). Both univariate and multivariate logistic regression analyses identified CAP values (p < 0.001) and glycosylated hemoglobin (HbA1c) levels (p < 0.001) as variables independently associated with prevalent CHD among patients with T2DM. The area under the ROC curve (AUC) for CAP in discriminating CHD status was 0.828, whereas the AUC for HbA1c was 0.695. Combined analysis of CAP and HbA1c yielded an AUC of 0.848. Although the absolute increase in AUC was modest, integrated discrimination improvement (IDI = 0.023, p = 0.038) and category‑free net reclassification improvement (NRI = 0.186, p = 0.041) indicated meaningful reclassification of CHD status, supporting the incremental value of the combined model. CAP, a quantitative indicator reflecting MASLD severity, is strongly associated with prevalent CHD in patients with T2DM. The combined assessment of CAP and HbA1c enhances the accuracy of CHD status discrimination in this population.
Glucolipotoxicity-induced β-cell dysfunction is a key factor in the pathogenesis of type 2 diabetes (T2D). While cholesterol is known to contribute to this dysfunction, the specific role of its major oxidation product, 7-ketocholesterol, remains unclear. We quantified serum 7-ketocholesterol levels using UPLC-MS in a cohort comprising individuals with T2D and normal glucose tolerance (NGT). Using INS-1 cells and primary islets, we investigated the effects of 7-ketocholesterol on β-cell function (including glucose-stimulated insulin secretion [GSIS], perfusion and calcium dynamics) and the underlying mechanisms related to oxidative stress (reactive oxygen species [ROS], mitochondrial membrane potential [MMP], ATP) and gene/protein expression. The antioxidant N-Acetyl-L-cysteine (NAC) was employed to rescue the observed dysfunction. Cohort analysis showed serum 7-ketocholesterol levels were significantly elevated in T2D patients compared to NGT controls (0.070 ± 0.035 vs. 0.051 ± 0.021 µmol/L), and this elevation correlated negatively with early-phase insulin secretion. In INS-1 cells and primary islets, 7-ketocholesterol exposure impaired GSIS and disrupted intracellular calcium signaling. Furthermore, 7-ketocholesterol induced marked oxidative stress, characterized by increased ROS production, loss of MMP, and reduced ATP levels. Mechanistically, 7-ketocholesterol promoted NRF2 nuclear translocation and upregulated the expression of antioxidant genes, including Gpx4 and Sod1. Critically, co-treatment with NAC attenuated 7-ketocholesterol-induced oxidative stress and restored insulin secretion and calcium signaling. Our findings suggest that elevated 7-ketocholesterol is associated with β-cell dysfunction in T2D patients and appears to impair insulin secretion by inducing oxidative stress in pancreatic β-cells, positioning 7-ketocholesterol as a potential contributor to diabetes progression.
The load-capacity index (LCI), defined as the ratio of fat mass to fat-free mass, represents a novel composite biomarker integrating metabolic load and functional capacity. This systematic review and meta-analysis aimed to determine the longitudinal association between LCI and incident cardiometabolic disease risk. We systematically searched PubMed, Embase, Web of Science, Cochrane Central, and Scopus from inception through January 2026 for longitudinal cohort studies reporting the association between LCI and cardiometabolic outcomes. Random-effects meta-analysis was performed using the DerSimonian-Laird method. Heterogeneity was assessed using Cochran’s Q, τ², and I² statistics. Study-specific log(HR) values and standard errors are reported in the Supplementary Material to enable full reproducibility. Eighteen longitudinal cohort studies comprising 129,777 participants and 5647 cardiometabolic events were included (mean follow-up: 11.4 years). Higher LCI was significantly associated with increased cardiometabolic risk (pooled HR = 1.174, 95
INSR-related insulin resistance is a form of monogenic diabetes caused by pathogenic variants in the INSR gene, resulting in impaired insulin receptor signalling and a spectrum of insulin resistance. Conventional diabetes management strategies relying on insulin sensitisation or augmentation are often less effective and evidence to guide treatment in those with heterozygous INSR mutations remains limited. A 63-year-old male diagnosed with type 2 diabetes aged 40 presented with a relatively stable fasting glucose and disproportionate postprandial hyperglycaemia despite prandial insulin. He had bilateral asymmetric mixed hearing loss (conductive/sensorineural) and early cardiovascular disease. C-peptide was preserved at 1.3 nmol/L with serum glucose at 7.1 mmol/L. Monogenic diabetes genetic testing identified a heterozygous likely pathogenic variant (i.e. mutation) in INSR (c.3473G > A, (p.Arg1158Gln)). Treatment with a sodium–glucose cotransporter-2 inhibitor (SGLT2 inhibitor) achieved 78
Diabetes mellitus and persistent proteinuria are major determinants of cardiovascular morbidity, graft dysfunction, and mortality after kidney transplantation. Although sodium-glucose cotransporter-2 (SGLT2) inhibitors have demonstrated substantial cardiorenal benefits in chronic kidney disease, data regarding their use in kidney transplant recipients remain limited. This study aimed to evaluate the clinical effects of dapagliflozin on proteinuria, graft function, glycemic measures, treatment burden, and observed safety events in diabetic kidney transplant recipients. We conducted an exploratory retrospective 1:1 clinically matched cohort study of diabetic kidney transplant recipients followed between 2010 and 2022. Among 282 transplant recipients, 68 had diabetes mellitus. Eighteen patients initiated dapagliflozin 10 mg/day and were included in the all-treated tolerability cohort; three discontinued treatment before completing 3 months because of patient preference unrelated to documented adverse events, leaving 15 recipients who received dapagliflozin for at least 12 months in the efficacy cohort. Fifteen diabetic kidney transplant recipients not receiving SGLT2 inhibitor therapy were selected as 1:1 clinically matched comparable controls according to prespecified matching criteria. Primary outcomes were changes in proteinuria and eGFR. Secondary outcomes included HbA1c, fasting plasma glucose, insulin requirements, antihypertensive medication burden, and observed safety events. Thirty diabetic kidney transplant recipients were included in the 12-month efficacy analysis (15 dapagliflozin-treated recipients and 15 1:1 clinically matched comparable controls). Baseline demographic, transplant-related, renal, and glycemic characteristics were broadly comparable between groups. Proteinuria decreased more in the dapagliflozin group than in controls (median change, − 157 [− 310 to − 52] vs. −12 [− 48 to + 25] mg/day; Hodges–Lehmann location-shift estimate, − 171 mg/day; 95
Myosteatosis is a marker of malnutrition and of adverse clinical outcomes and diabetes is among its contributors. Currently, no single universally accepted method exists to screen for malnutrition, but COntrolling NUTritional status (CONUT) score seems to be promising. This study aimed to assess the impact of myosteatosis on in-hospital outcomes and to test its association with CONUT score in people with and without type 2 diabetes. 227 patients aged > 40 years admitted to an Internal Medicine Department were consecutively recruited, recording in-hospital outcomes. Myosteatosis was assessed as multifidus muscle to subcutaneous fat (MM/F) attenuation ratio at computed-tomography scan. CONUT was calculated using albumin, lymphocyte count and total cholesterol. The population was stratified, based on sex-differentiated tertiles of MM/F, in a low myosteatosis group (n = 152) and a high myosteatosis group (n = 75; top tertile of MM/F). The high myosteatosis group showed a higher prevalence of in-hospital death (12.5 vs. 26
Management of type 1 diabetes (T1D) in correctional facilities is challenging due to limited autonomy, restricted access to technologies, and non-flexible daily routines. To evaluate the feasibility and short-term glycemic outcomes of advanced hybrid closed-loop (aHCL) systems in individuals with T1D in a correctional setting. We conducted a retrospective real-world case series including adults with T1D incarcerated in a correctional facility and initiated on an advanced hybrid closed-loop (aHCL) system. Glycemic metrics were assessed at baseline and after 3 months. Continuous variables are reported as median (IQR). Paired comparisons were performed using the Wilcoxon signed-rank test. Six individuals were included and five completed follow-up. Median HbA1c decreased from 9.7
Cardiovascular risk stratification at the time of type 2 diabetes diagnosis remains challenging. We evaluated the incidence and baseline predictors of first-ever major adverse cardiovascular events (MACE) in patients with newly diagnosed type 2 diabetes without overt complications. We conducted a prospective cohort study of 937 consecutive adults with newly diagnosed type 2 diabetes, free of overt diabetic complications and pre-existing cardiovascular disease at baseline, followed for a mean of 62.7 ± 21.5 months. Baseline assessment included fasting C-peptide, transcutaneous oxygen tension (TcPO2), structured therapeutic patient education (TPE), and conventional metabolic and cardiovascular variables. Incident MACE was analyzed using Cox proportional hazards regression, and receiver operating characteristic analysis was used to derive an exploratory C-peptide cut-off. During follow-up, 42 participants (4.5
Diabetic kidney disease (DKD) is driven by persistent metabolic stress, immune dysregulation and progressive renal fibrosis. PRDM16 is a metabolic transcriptional regulator involved in adipose remodeling, mitochondrial activity and tissue homeostasis, but whether myeloid PRDM16 links diabetic metabolic stress to macrophage polarization and renal fibrosis remains unclear. Public DKD transcriptomic datasets were analyzed to identify PRDM16-associated immune and macrophage signatures. Myeloid PRDM16-deficient mice and littermate controls were used to establish experimental DKD. Renal injury, fibrotic remodeling, macrophage polarization and PI3K/AKT signaling were evaluated by histological staining, immunostaining, ELISA, qRT-PCR and western blotting. High glucose-stimulated BMDMs and THP-1-derived macrophages were used for mechanistic validation, and LY294002 was applied to inhibit PI3K/AKT signaling. Bioinformatic analysis linked PRDM16 expression with macrophage-related immune features in DKD. In vivo, myeloid PRDM16 deficiency aggravated renal matrix accumulation, collagen deposition and α-SMA/Collagen-I expression. PRDM16 loss promoted a shift from M2-like macrophages toward M1-like inflammatory macrophages, characterized by increased CD80, CD86, NOS2, TNF-α and IL-1β, together with reduced CD206, Arg1, Fizz1, IL-10 and IL-4. Mechanistically, PRDM16 deficiency enhanced PI3K/AKT phosphorylation in macrophages, whereas LY294002 partially reversed M1-like polarization and attenuated renal inflammation and fibrosis. Myeloid PRDM16 acts as a metabolic-immune regulator that restrains M2-to-M1 macrophage polarization and limits renal fibrotic progression in DKD. Loss of PRDM16 aggravates macrophage-driven inflammation and fibrosis partly through PI3K/AKT activation, suggesting that the PRDM16–PI3K/AKT axis may represent a potential target for macrophage-directed intervention in diabetic kidney disease.
Sodium–glucose cotransporter 2 inhibitors (SGLT2i) increase haematocrit and may cause erythrocytosis, creating uncertainty in type 2 diabetes management. Most available data derive from administrative registries or mixed, non-diabetic and/or non-European population. This study aimed to assess the onset, clinical characteristics and management outcomes of people with type 2 diabetes developing SGLT2i-associated erythrocytosis in a routine clinical setting. This retrospective, single-centre cohort study included adults with type 2 diabetes who developed at least one episode of erythrocytosis (haematocrit ≥ 48
Non-alcoholic fatty liver disease (NAFLD) is a prevalent systemic metabolic disorder closely linked to obesity and type 2 diabetes mellitus (T2DM). Circulating microRNAs have emerged as potential biomarkers reflecting disease progression and metabolic risk. This study aimed to investigate the clinical, biochemical, and molecular profiles of NAFLD patients, focusing on miRNA-155-3p and miRNA-192-5p, and to evaluate their diagnostic and predictive value. A total of 200 participants were enrolled: 50 healthy controls, 50 NAFLD, 50 NAFLD with obesity, and 50 NAFLD with T2DM. Clinical, biochemical (liver enzymes, lipid profile, HOMA-IR, CRP, 25(OH) vitamin D) and circulating miRNA levels were measured. Statistical analyses included Kruskal-Wallis tests, ROC curves, and univariate and multivariate multinomial logistic regression. NAFLD patients, particularly with obesity and T2DM, showed elevated BMI, SGPT/SGOT, cholesterol, TG, LDL, HOMA-IR, and CRP (p < 0.001), and reduced vitamin D (p < 0.001). miRNA-155-3p and miRNA-192-5p were significantly upregulated (Kruskal-Wallis, p < 0.001). ROC analysis showed: miRNA-155-3p, AUC = 0.763, specificity 100
Blood pressure is regulated in part by circadian rhythms, and melatonin has been reported to exert blood pressure–lowering effects. The underlying mechanisms, however, remain unclear. We hypothesized that melatonin would lower blood pressure in individuals with type 2 diabetes with or without hypertension, and that this effect would be mediated by a reduction in arterial stiffness. We conducted a double-blinded, randomized, placebo-controlled crossover trial involving 17 individuals with type 2 diabetes. Participants completed two treatment phases: three months of 10 mg melatonin taken one hour before nighttime, and three months of placebo taken at the same time separated by a four-week washout period. On the last day of each period, participants underwent 24-hour ambulatory blood pressure monitoring, including measurement of arterial stiffness, using the Arteriograph 24. Fifteen participants completed the 24-hour ambulatory blood pressure monitoring (hypertension n = 6). Melatonin treatment was associated with numerical, non-significant reductions in mean nighttime systolic blood pressure (-6 [-13:1] mmHg, p = 0.08, ≈ 5
Type 2 diabetes (T2D) is a complex chronic disease often associated with other metabolic conditions that increase the risk of cardiovascular (CV) disease and early mortality. Hence, early, integrated management of T2D may prevent long-term CV complications. To determine the appropriateness of early multifactorial intervention in people with T2D we conducted an online modified Delphi study. The study involved a multidisciplinary panel of 17 Italian experts, ensuring maintenance of study design and rigorous execution throughout the consensus process, in line with the core principles of Delphi studies. Main areas of investigation included: (1) targets of disease control for adults with T2D; (2) early treatment, CV risk assessment, and multi-factorial strategy; (3) unmet needs, including treatment adherence; and (4) public health aspects. Consensus was unanimous (100
Familial Hypercholesterolemia (FH) is highly prevalent in humans. To date, the need for genetic testing is indicated by widely used clinical scores (different for adults and children) that support the diagnosis of FH. The performance of genetic testing is a matter of debate and is likely dependent on different clinical, ethnic and environmental contexts, with sparse data from Italy. Our aims were to evaluate: (i) the performance of genetic testing in Italian patients with a clinical diagnosis of FH; (ii) the role of clinical features on the genetic testing performance. Pathogenic (P) or likely pathogenic (LP) variants in ABCG5, ABCG8, APOB, APOE, LDLR, LDLRAP1, LIPA, PCSK9 were investigated by WES and confirmed by Sanger sequencing. The pick-up rate was 39.8
Adults with coexistent diabetes mellitus and hypertension (DM-HTN) have a substantially elevated risk of all-cause mortality. Physical activity (PA) is a key modifiable factor, yet conventional self-reported or categorical measures may fail to capture clinically relevant variation. We investigated associations between sensor–derived continuous PA dimensions and all-cause mortality in DM-HTN. We analysed 4,294 DM-HTN and 1,482 diabetes-alone adults from the UK Biobank (median follow-up 85.2 months; 731 deaths) and 530 DM-HTN and 235 diabetes-alone participants from NHANES 2011–2014 (mean follow-up 63.5 months; 123 deaths), all with device-measured wrist accelerometry. Continuous sensor-derived metrics included Daily MET/MIMS (volume) and Peak-30 MET/MIMS (peak intensity). Associations with all-cause mortality were examined using multivariable Cox regression, restricted cubic spline modelling, and GBDT models with SHAP attribution. Both continuous PA dimensions were independently associated with all-cause mortality in the DM-HTN group across cohorts. In the UK Biobank, fully adjusted hazard ratios were 0.66 for Daily MET and 0.43 for Peak-30 MET. In NHANES, Peak-30 MIMS showed robust associations (HR = 0.57, p < 0.001), while Daily MIMS attenuated to non-significance (HR = 0.95, p = 0.116) after full adjustment. Non-linear dose–response modelling identified lower inflection points for peak intensity in DM-HTN compared with diabetes-alone individuals. SHAP analyses confirmed that continuous peak intensity maintained stable protective contributions across comorbidity strata. Wearable sensor-derived continuous PA dimensions capture mortality risk gradients in DM-HTN that are inaccessible to conventional approaches. Population-specific, clinically attainable inflection thresholds identified through continuous monitoring support incorporating sensor-derived PA metrics as digital biomarkers in comorbidity-specific risk stratification frameworks.
We aimed to compare heart rate variability (HRV) between adolescents with type 1 diabetes and healthy age- and sex-matched control participants. We were also interested in how HRV may change during puberty. Eighty-five adolescents with type 1 diabetes (mean diabetes duration 7.0 ± 3.6 years) and 103 healthy age- and sex-matched youths consented to this cross-sectional study. We derived HRV data for time domain and power spectra analyses from Holter recordings (mean duration 17.8 h) and analyzed associated risk factors for HRV deterioration during total recording time and nighttime separately. Total low frequency (LF) and very low frequency (VLF) domains (ms2) were significantly lower in children with type 1 diabetes than in healthy controls (LF, P = 0.049 and VLF, P = 0.005, respectively), whereas no differences were found in the measurements taken at night. The most significant predictors for untoward changes in power spectra were skinfold sum and lipids. Mean heart rate (beats/min), or any of the time domain variables did not differ significantly between study groups. Compared with those in the lowest HbA1c tertile, adolescents with type 1 diabetes in the highest HbA1c tertile had significantly lower LF and VLF power spectra results. Adolescents with type 1 diabetes have depressed HRV from low to very low frequencies. Deterioration of autonomic nervous system function in adolescents with type 1 diabetes, measured with HRV power spectra is mainly associated with metabolic factors, although it is not possible to establish causal links between these variables.
Tinnitus is a common and often debilitating condition that substantially affects quality of life. While diabetes has been suggested as a potential risk factor, the relationship remains poorly understood, particularly in large population-based settings where classification of diabetes type often relies on algorithms rather than confirmatory biomarkers. The recent UK Biobank study by Ji and colleagues addresses this gap by reporting that type 2 diabetes is associated with higher tinnitus prevalence. While the study benefits from a large sample and systematic examination of diabetes-related factors, two methodological concerns warrant consideration before the findings are interpreted as robust evidence. First, diabetes type was determined using algorithmic classification without confirmatory biomarkers such as autoantibodies or C-peptide. Second, the analytical strategy treated age as a simple covariate, implicitly assuming that the diabetes–tinnitus association remains constant across the entire 40–70 year age range. While the study offers valuable hypothesis-generating data, these methodological considerations suggest that the reported associations should be interpreted cautiously until confirmed by biomarker-validated phenotyping and more flexible analytical approaches that account for age-related heterogeneity.
