Metabolic dysfunction-associated steatotic liver disease (MASLD) is closely linked to obesity, insulin resistance and type 2 diabetes mellitus (T2DM). Selective sodium-glucose cotransporter 2 (SGLT2) inhibitors have established glycaemic, renal and cardiovascular benefits, but their hepatic effects in MASLD and metabolic dysfunction-associated steatohepatitis (MASH) remain incompletely defined. We conducted a PRISMA 2020 systematic review and meta-analysis of randomized controlled trials evaluating selective SGLT2 inhibitors in adults with MASLD, MASH or corresponding earlier non-alcoholic fatty liver disease/non-alcoholic steatohepatitis phenotypes. The protocol was registered in PROSPERO (CRD420261390850). Thirty randomized trials, including 2359 participants contributing to liver-outcome analyses, were included. Most evidence came from T2DM-associated MASLD trials. In a prespecified strict MR-based synthesis of two directly extractable double-blind placebo-controlled trials including 116 participants, SGLT2 inhibition reduced liver fat compared with placebo: mean difference - 2.54% points, 95% confidence interval - 4.39 to - 0.69; I²=41.2%. Certainty was rated as low because of serious indirectness and serious imprecision; publication bias could not be formally assessed because only two trials contributed to the pooled analysis. Additional placebo-controlled magnetic resonance evidence supported liver fat reduction in non-diabetic MASLD but was not pooled because of median-based reporting. Three biopsy-based randomized trials enrolled 245 participants overall, of whom 229 contributed evaluable data to the histological fibrosis-improvement meta-analysis. This analysis suggested a higher likelihood of histological fibrosis improvement: risk ratio 2.21, 95% confidence interval 1.52-3.23; I²=0%, but the finding was judged low certainty and hypothesis-generating. Elastography-based fibrosis-related outcomes were heterogeneous and should not be equated with histological fibrosis regression. SGLT2 inhibitors also improved body weight, body mass index, visceral adiposity and glycaemic control in T2DM-associated MASLD. Current evidence is most consistent with a modest but reproducible reduction in imaging-assessed hepatic steatosis, particularly in T2DM-associated MASLD, whereas evidence for histological disease modification remains preliminary. SGLT2 inhibitors should therefore be regarded primarily as cardiometabolic agents with liver fat-lowering effects and possible adjunctive hepatic relevance, rather than established liver-specific disease-modifying therapies for MASLD/MASH. Registration: PROSPERO CRD420261390850.
Type 2 diabetes mellitus (T2DM) is increasingly recognized as a major risk factor for cognitive impairment and dementia, extending beyond its traditional metabolic complications. Emerging evidence suggests that cognitive decline in T2DM arises from a complex interplay among gut dysbiosis, chronic inflammation, impaired insulin signaling, blood-brain barrier dysfunction, and mitochondrial abnormalities. The gut-brain-mitochondria (GBM) axis has recently emerged as an integrated mechanistic framework linking peripheral metabolic disturbances to central neurodegenerative processes. Within this axis, alterations in gut microbial composition and function promote intestinal barrier disruption, endotoxemia, and aberrant production of microbial metabolites, which collectively contribute to systemic inflammation, neuroinflammation, and neuronal insulin resistance. Mitochondria occupy a central position in this network by regulating cellular bioenergetics, redox homeostasis, calcium signaling, and neuronal survival. Mitochondrial dysfunction amplifies oxidative stress, impairs synaptic plasticity, disrupts adult hippocampal neurogenesis, and accelerates neurodegenerative signaling pathways associated with cognitive decline. Furthermore, bidirectional communication between gut-derived metabolites and mitochondrial pathways influences neuronal resilience and disease progression. This review synthesizes current evidence describing the mechanistic convergence of gut dysbiosis, mitochondrial dysfunction, and neuroinflammation in T2DM-associated cognitive impairment. We also discuss emerging biomarkers, including mitochondrial DNA copy number, circulating lactate, lipopolysaccharide, zonulin, and microbial metabolite signatures, that may facilitate early disease detection and patient stratification. Finally, we critically evaluate therapeutic strategies targeting the GBM axis, including microbiota-directed interventions, mitochondrial-targeted antioxidants, metabolic modulators, and lifestyle-based approaches. Understanding the integrated role of the GBM axis may provide novel opportunities for precision-based interventions to prevent or slow diabetes-associated cognitive decline.
Progressive pancreatic β-cell dysfunction constitutes a hallmark of type 2 diabetes (T2D), yet the molecular programmes governing metabolic fitness deterioration remain incompletely characterised at single-cell resolution. Single-cell transcriptomic data (GSE221156) encompassing pancreatic islet cells from 48 donors (non-diabetic [ND], n = 17; pre-diabetic [PD], n = 14; T2D, n = 17) were analysed using an interpretable machine learning framework that integrated sparse rule-based classification, pathway-constrained modelling, and mitochondrial fitness indexing. Five transcriptionally distinct β-cell subtypes (β1-β5) were resolved. The β1 subtype exhibited peak proportional representation in PD donors (35.0%) compared with ND (16.7%) and T2D (21.1%), consistent with stress-induced adaptive expansion. Mitochondrial biogenesis and ER stress emerged as the top-ranked programmes discriminating T2D from ND β-cells (importance scores = 0.329 and 0.329). Within the mitophagy gene set, MFN2 exhibited the highest feature importance (|logFC| = 0.472), followed by PINK1 (|logFC| = 0.199). PINK1 expression progressively declined across β1→β5 subtypes. A mitochondrial fitness index integrating mitophagy, proteostasis, biogenesis, and oxidative phosphorylation achieved R² = 0.65 against module-based quality scores. Hypergeometric enrichment analysis of differentially expressed genes between the adaptive β1 subtype and dysfunctional β2-β5 subtypes revealed significant enrichment of insulin secretion (p = 0.0019), endoplasmic reticulum stress (p = 0.0013), and oxidative phosphorylation (p = 0.045) pathways. PINK1-centred mitophagy represents a critical determinant of β-cell metabolic fitness in T2D, with implications for therapeutic strategies aimed at preserving islet function during disease progression.
This study aimed to evaluate the reliability of haemoglobin A1c (HbA1c) for assessing glycaemic status in patients with type 2 diabetes mellitus (T2DM) and secondary polycythaemia, and to determine whether fructosamine serves as a more reliable complementary glycaemic marker in this population. In this prospective observational study, patients with T2DM and secondary polycythaemia (n = 62) and T2DM controls with normal haematological indices (n = 40) were enrolled. HbA1c- and fructosamine-derived estimated mean plasma glucose (eMPG) were compared with structured home capillary blood glucose (CBG; 7 measurements/day × 5 days). Bland-Altman analysis and multivariate linear regression (adjusting for age, sex, diabetes duration, BMI, smoking, fasting glucose, haemoglobin, haematocrit) were performed. Fasting plasma glucose and HbA1c were similar between groups (p = 0.352 and p = 0.816), while fructosamine (456.53 ± 90.18 vs. 404.18 ± 97.63 µmol/L; p = 0.001) and Home-CBG (207.23 ± 49.18 vs. 181.98 ± 55.31 mg/dL; p = 0.002) were significantly higher in the polycythaemia group. Bland-Altman analysis confirmed a systematic negative bias of HbA1c-derived eMPG (mean bias: -23.73 mg/dL; 95% LoA: -45.97 to - 1.48). On multivariate regression, polycythaemia group assignment was the strongest independent association with HbA1c underestimation (β=-16.80 mg/dL; 95% CI: -25.53 to - 8.07; p < 0.001). Fructosamine-derived eMPG showed substantially better agreement with Home-CBG (bias: +7.68 mg/dL). Overall, 60% of polycythaemia patients would have been assigned to a different glycaemic control category based on fructosamine versus HbA1c. HbA1c systematically underestimates glycaemic status in patients with polycythaemia and may lead to clinically relevant misclassification. In contrast, fructosamine appears to provide a more reliable estimate of glycaemic control in this population.
Type 2 diabetes mellitus develops when insulin resistance raises insulin demand and pancreatic beta cells fail to sustain insulin supply. Genome-wide association studies support a polygenic architecture and enrich for loci that affect beta cell stimulus secretion coupling and secretory stress responses. Polygenic risk scores summarize liability across many variants and guide genetic stratification in cohort studies. This review uses TCF7L2 and CDKAL1 as two mechanistically interpretable loci to connect inherited variation to measurable physiology. TCF7L2 risk alleles reduce incretin potentiation of insulin secretion after oral nutrient exposure, which blunts early postprandial insulin release. CDKAL1 risk alleles impair the ms2 modification of t6A37 at position 37 of tRNALys(UUU), which increases proinsulin mistranslation and raises endoplasmic reticulum stress in beta cells. These defects converge during repeated postprandial cycles that require rapid insulin synthesis and secretion. Reduced incretin signaling prolongs glycemic excursions and increases secretory workload, which intensifies folding stress when translation quality control is limited. The model predicts earlier postprandial dysglycemia under obesity or aging related insulin resistance and faster loss of beta cell reserve when both pathways constrain supply. The framework supports mechanistic phenotyping and pharmacogenetic testing within a broader polygenic risk setting.
Although continuous glucose monitoring (CGM) devices are now standard of care among Type 1 diabetes patients, they are still relatively underutilized in Type 2 diabetes (T2D), particularly in those patients not treated with insulin. Widespread adoption continues to be hindered by a combination of factors. Chief among these is the scarcity of long-term, large-scale clinical trials demonstrating the benefits of the use of CGM in T2D. This meta-analysis aimed to address this gap by comparing CGM with self-blood glucose monitoring (SBMG), with primary outcomes of HbA1c and time in range (TIR) in insulin-treated and non-insulin-treated TD2 patients. Following the stringent rules mandated by our National Health Service (which requires a panel composed of all stakeholders involved in diabetes treatment, and includes PICO, GRADE, AGREE, and meta-analyses), we performed a systematic review of RCTs that enrolled two groups of individuals with T2D, those treated with insulin (including basal and basal-bolus regimens), and those receiving treatments other than insulin. All included trials compared CGM with structured blood glucose monitoring (SBGM) with glycated hemoglobin (HbA1c) as the main endpoint. Based on the strength and consistency of the evidence, the panel issued a strong recommendation in favor of CGM for individuals with T2D treated with insulin (including those on basal insulin alone) and for individuals with T2D not treated with insulin, particularly for those with glycated hemoglobin levels ≥ 7%. From a pharmacoeconomic perspective, outcomes were positive in both patient groups. CGM represents a clinically effective and cost-efficient approach to optimizing glycemic control in T2D, becoming mandatory among individuals on insulin therapy. Our findings support a shift in clinical practice toward the more widespread use of CGM in T2D, with regulatory frameworks and reimbursement policies needing to adapt accordingly.
Immune ageing, characterized by a decline in immune function and increased chronic inflammation, significantly impacts tissue repair mechanisms, particularly in diabetic wounds. Diabetic individuals often experience delayed wound healing due to impaired immune responses and persistent inflammation, making effective management of chronic wounds a challenge. Recent studies suggest that micronutrients, which play an essential role in modulating immune responses and inflammatory pathways, have the potential to mitigate these age-related dysfunctions and improve wound healing outcomes. This review explores key micronutrients, including Vitamin D, Vitamin C, Zinc, and Selenium, in enhancing immune function and promoting tissue repair in diabetic wound healing. We discuss how deficiencies in these micronutrients contribute to increased inflammation, delayed immune responses, and prolonged wound healing. Furthermore, we examine emerging micronutrients and their potential therapeutic benefits, such as Magnesium, Folic Acid, and Curcumin, in reducing oxidative stress and modulating immune function. In addition, innovative delivery systems, including liposomal encapsulation and nanotechnology, are highlighted as promising strategies to enhance the bioavailability and efficacy of micronutrients, ensuring their optimal therapeutic effect in ageing and diabetic populations. By synthesizing current evidence and proposing future research directions, this review emphasizes the importance of micronutrient supplementation as a therapeutic strategy to address immune ageing and accelerate wound healing, offering new opportunities for managing chronic diabetic wounds and related complications in the ageing population.
Recent data have discussed occurrence of phimosis with Sodium-glucose co-transporter-2 (SGLT2) inhibitors. However, the potential risk among the different SGLT2 inhibitors is unknown. Using Individual Case Safety Reports (ICSRs) registered in the WHO pharmacovigilance database (01/01/2000-30/06/2025), comparisons between the different SGLT2 inhibitors and versus other drugs used in diabetes (DUD) were performed. Results are shown as Reporting Odds Ratios (ROR). Among 11 342 810 ICSRs, 227 were phimosis/paraphimosis with SGLT2 inhibitors, mainly between 45 and 64 years. The higher ROR value was found with empagliflozin followed by dapagliflozin and canagliflozin. ROR for SGLT2 inhibitors was higher that of all other DUD [34.72 (25.86-46.62)]. The reporting risk of phimosis/paraphimosis with SGLT2 inhibitors was also higher than that of each pharmacological class of DUD. The results suggest an association between SGLT2 inhibitors use and phimosis ICSRs. Empagliflozin had the higher reporting risk.
The global rise in diabetes mellitus has been accompanied by a marked increase in associated complications, most notably impaired wound healing. Diabetic non-healing wounds arise from multifactorial pathophysiological mechanisms, including excessive and prolonged inflammation, immune dysregulation, impaired angiogenesis, defective fibroblast-to-myofibroblast transition and aberrant growth factor signaling. These abnormalities delay wound contraction and re-epithelialization, increasing susceptibility to infection, chronic ulceration and limb amputation. Traditional and complementary approaches such as herbal formulations, Ayurvedic practices, and natural bioactive compounds have demonstrated potential in mitigating oxidative stress, modulating inflammation and promoting neovascularization. In parallel, advanced technological interventions, including nanocomposite hydrogels, smart and responsive biomaterials, gene therapy and targeted growth factor delivery systems, are being developed to create a pro-regenerative wound microenvironment. Modern clinical strategies such as electromagnetic therapy, negative pressure wound therapy, electrospun nanofiber scaffolds and 3D/4D bioprinting further contribute to enhanced wound contraction and tissue regeneration. Additionally, bioengineered skin substitutes, stem cell-based therapies and innovative growth factor delivery platforms offer promising translational prospects. This review critically summarizes traditional, complementary, and innovative approaches reported up to 2025, with an emphasis on smart biomaterials, emerging therapies and relevant preclinical models, highlighting future directions for improving diabetic wound care and patient quality of life.
the use of Automated Insulin Delivery (AID) systems has increased in pregnant women with type 1 diabetes (DM1). To date, little data exist regarding glucose control and insulin modifications with AID in automode during delivery and in the postpartum period. we retrospectively evaluated pregnancy-specific metrics and insulin variations in a short peripartum period in 14 DM1 users of the MiniMed™780G pump in closed loop mode from pregestational care to the postpartum period. glycemic control during labour and delivery was optimal, with Time In Range 63-140 mg/dl (pTIR) did not significantly change, remaining nearly the same from 48 h before to 48 after the time of birth (85%). Variations in the Total insulin daily dose (TDD) were mainly influenced by manual boluses rather than the autobasal insulin in all examined periods. Auto basal insulin + autocorrection boluses reduced by 17.5% immediately after delivery and by 31% in the early postpartum period (14 days). this is the first study to report on insulin variations with an AID system in automode during the strict peripartum period, before and after the time of birth. pTIR did not significantly change, remaining nearly the same from 48 h before to 48 after the time of birth, despite the dramatic variations in insulin requirements, with unexpected little variation in autobasal insulin. It is possible that, for patients with very good glycemic control using MinimedTM780G, the manual basal rate needs to be reduced less than the usual 50% after delivery, if switching to manual mode for any reason. Further research is needed to develop a protocol for glucose management in women with AID systems during and after delivery.
To investigate whether migration background is associated with diabetes technology use at diagnosis and during follow-up in children and adolescents with type 1 diabetes. This cross-sectional study included children and adolescents aged 4-19 years with type 1 diabetes duration ≥ 1 year. Insulin pump therapy at diagnosis and diabetes technology use at follow-up (defined as insulin pump therapy or automated insulin delivery [AID]) were compared between participants with and without migration background. Multivariable logistic regression was used to assess factors associated with technology use. A total of 143 participants (mean age 13.2 ± 3.7 years) were included, of whom 24.5% had a migration background. At diabetes onset, insulin pump therapy was less frequent in participants with migration background compared to those without (28.6% vs. 50.0%, p = 0.027). At follow-up, diabetes technology use was numerically lower in participants with migration background (60.0% vs. 76.8%); however, the difference did not reach statistical significance (p = 0.052). In adjusted analyses, migration background was not significantly associated with diabetes technology use at follow-up (OR 2.33, 95% CI 0.92-5.89), whereas younger age and longer diabetes duration were independently associated with technology use. Children with migration background were less likely to receive insulin pump therapy at diagnosis. At follow-up, differences in diabetes technology use were smaller and not statistically significant. These findings are consistent with the hypothesis of delayed technology uptake, although longitudinal studies are required to determine the timing of diabetes technology initiation.
This randomized controlled trial examined whether benefits achieved during supervised resistance training (SRT) were sustained after transitioning to self-managed home-based training in older adults with type 2 diabetes mellitus (T2DM) and sarcopenia. In this single-center, parallel-group trial, adults aged ≥ 65 years with T2DM and sarcopenia were randomized 1:1 to a 24-week resistance-training intervention or control. The intervention comprised 12 weeks of SRT followed by 12 weeks of self-managed home-based training. Co-primary outcomes were skeletal muscle index (SMI), handgrip strength (HGS), five-times-sit-to-stand (5TSTS), and SARC-CalF score. Secondary outcomes were HbA1c and SF-12 physical and mental component summary scores. Longitudinal changes were evaluated using generalized estimating equations. Sixty-two participants were randomized (median age, 72 years; 67.7% female). At 12 weeks, SRT significantly improved HGS, 5TSTS performance, and SARC-CalF score, whereas SMI showed no significant between-group difference. At 24 weeks, SMI showed a modest favorable change, but earlier improvements in HGS, 5TSTS performance, and SARC-CalF score were attenuated after transition to self-managed training. SF-12 scores showed supportive, favorable patterns through 24 weeks, whereas HbA1c showed no clear intervention-related change. In older adults with T2DM and sarcopenia, transition from SRT to self-managed home-based training produced outcome-specific effects. Functional gains diminished after supervision ended, whereas SMI showed a modest, delayed, favorable change. These findings suggest that hybrid support models incorporating periodic supervision, remote monitoring, automated reminders, and feedback-guided exercise logs may be needed to sustain adherence, exercise quality, and functional capacity. Retrospectively registered at ClinicalTrials.gov (NCT07398495), February 23, 2026.
To develop a predictive model for coronary atherosclerosis progression in patients with type 2 diabetes mellitus (T2DM) based on Artificial intelligence(AI)-derived coronary computed tomography angiography (CCTA) parameters combined with clinical indicators. This retrospective study enrolled 114 patients with T2DM and non-obstructive coronary artery disease (1%-49% stenosis) who underwent CCTA at our hospital between September 2019 and September 2024. After follow-up of 1-5 years, patients were stratified into a progression group (n = 48) and a control group (n = 66). Progression was defined as the occurrence of acute myocardial infarction, revascularization, or stenosis progression to ≥ 50% on follow-up CCTA. Clinical data and AI-derived quantitative parameters of pericoronary adipose tissue(PCAT) and coronary plaques were compared. A predictive model was then developed using stepwise logistic regression and its performance evaluated. The progression group had significantly higher glycated hemoglobin (HbA1c) and troponin, and lower high-density lipoprotein cholesterol (HDL-C) (all P < 0.05).CCTA analysis revealed that the progression group had a significantly greater pericoronary fat attenuation index around the left anterior descending (LAD-FAI) and left circumflex (LCX-FAI) arteries, as well as increased plaque length, total plaque volume, and specific plaque component volumes (all P < 0.05). Multivariate logistic regression analysis identified HbA1c, LAD-FAI, and plaque length as independent predictors of progression. A nomogram based on these predictors achieved an AUC of 0.8332. LAD-FAI and plaque length and HbA1c are independent predictors for the progression of non-obstructive coronary lesions in T2DM patients. The proposed nomogram may provide a noninvasive and cost-effective tool for early risk stratification and preventive management.
Italy is a major hub for migration routes. Disparities in health management across different geographic regions, particularly among individuals with type 2 diabetes mellitus (T2D), are well recognized, yet comprehensive data on the quality of T2D care in migrant populations remain limited. Quality indicators of T2D care were analyzed for foreign patients compared with European patients using the 2022 AMD Annals database. The Italian National Institute of Statistics classification defined geographic origins. Data on country of origin were available for 179,536 T2D patients, with 19.3% being foreign, mainly from North Africa, Central and Eastern Europe, Central and South Asia, Central and South America.Foreign T2D patients were generally younger, resulting in shorter disease duration. While annual screening rates for risk factors and major complications were as European subjects, critical gaps were noted in microalbuminuria and retinopathy assessments. Treatment intensity was lower for patients from North and West Africa and Central and South Asia, though the use of innovative therapies like GLP-1RAs and SGLT2i was comparable to European patients. The overall quality of care, measured by the Q-score, was lowest in West African patients (26.4 ± 9.1 vs. 29.1 ± 8.0), while 51.6% of those from Central and South Asia had satisfactory care quality (Q-score > 25). Study showed differences in age, disease duration, and treatment among patients from various geographic regions, while indicating equitable access to therapies and comparable overall quality of care. These findings may inform management strategies to improve T2D care for migrant populations.
To investigate the independent association between long-term glycemic variability, measured as the coefficient of variation (CV) of HbA1c, and the presence of diabetic retinopathy (DR) in a cohort of adults with diabetes within a systematic eye screening program. This study screened 379 adults with type 1 and type 2 diabetes. Long-term glycemic variability was calculated as the CV of serial HbA1c measurements. DR was assessed via dilated fundus photography. The association between HbA1c CV and DR was analyzed using multivariable logistic regression adjusting for confounders. DR incidence of 12.4%, mostly mild non-proliferative. The median HbA1c CV was 7.0% (53 mmol/mol). In unadjusted bivariate analysis, the incidence of mild DR was higher in the low- glycemic variability group (CV < 5%) compared to the high- glycemic variability group. However, the multivariable logistic regression analysis revealed that higher HbA1c CV was independently associated with the presence of DR (β = 0.643, P = 0.042), alongside diabetes duration (P < 0.001) and age (P < 0.001). In conclusion, in a cohort of individuals with both type 1 and type 2 diabetes and a low incidence of DR, long-term glycemic variability, estimated as HbA1c CV, was independently associated with an increased risk of this complication.
This systematic review synthesizes current evidence on circulating microRNAs (miRNAs) associated with diabetic retinopathy (DR) in individuals with type 2 diabetes (T2D). DR is a leading cause of vision impairment among adults with diabetes. Identifying circulating miRNAs as minimally invasive biomarkers could enable early DR detection, improve disease monitoring, and support therapeutic development. Following PRISMA guidelines, PubMed and Scopus were systematically searched for English-language studies published between January 2014 and 20 July 2024. Observational studies reporting quantitative expression data (fold-change) of circulating miRNAs in serum or plasma samples from patients with DR and T2D controls were included. Data extraction and quality assessment were independently performed by two reviewers. From 957 screened records, 16 studies met all inclusion criteria. Most studies were conducted in Chinese cohorts and collectively identified numerous differentially expressed miRNAs implicated in NF-κB signaling, PI3K/Akt signaling, angiogenesis, and neuronal apoptosis. Several miRNAs, including hsa-miR-155, hsa-miR-320a, hsa-miR-320b and hsa-miR-338-3p showed consistent dysregulation across multiple studies and demonstrated promise as non-invasive biomarkers for DR diagnosis and progression monitoring. However, heterogeneity in study design, small sample sizes, and limited validation experiments reduced comparability across studies. Current evidence supports the potential of circulating miRNAs as biomarkers for early detection and monitoring of DR in T2D. Nevertheless, larger, multiethnic, and longitudinal studies with standardized protocols, coupled with mechanistic and functional validation, are essential to confirm their diagnostic and therapeutic utility.
To synthesise the bidirectional evidence on the association between obstructive sleep apnea (OSA) and diabetic retinopathy (DR), separating studies framing OSA as the exposure for DR (Arm 1) from studies framing DR as the exposure for OSA (Arm 2). Systematic review and meta-analysis of observational studies (PROSPERO: CRD420251135427). PubMed, Scopus, Web of Science, and Google Scholar were searched from inception to July 13, 2025, supplemented by structured re-screening of five prior systematic reviews and forward and backward citation searching. Eligible studies enrolled individuals with diabetes mellitus and reported binary OSA (or, in Arm 2, DR) exposure with an unexposed comparator. Within each arm, exposure and outcome were severity-stratified; unadjusted and adjusted odds ratios (ORs) were pooled separately using random-effects models in MetaAnalysisOnline.com. Risk of bias was assessed with the Newcastle-Ottawa Scale (NOS) and certainty of evidence with the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) framework. Twenty-six studies met eligibility criteria. In Arm 1 (OSA → DR), the unadjusted pooled OR for any DR with OSA classified as a binary exposure was 2.41 (95% confidence interval [CI] 1.53-3.80; 10 studies; very low certainty), but attenuated to 1.03 (95% CI 0.64-1.66; 2 studies; low certainty) in confounder-adjusted analyses. OSA-severity-stratified Arm 1 estimates for mild, moderate, and severe OSA were directionally consistent but not statistically significant in either unadjusted or adjusted pooling. DR-stage-specific Arm 1 analyses (background DR, mild/moderate/severe non-proliferative DR [NPDR], proliferative DR [PDR]) were directionally aligned with the overall Arm 1 finding but imprecise. In Arm 2 (DR → OSA), pooled estimates showed inverse or null associations across DR severity strata; severe OSA as an outcome of DR yielded a pooled OR of 1.24 (95% CI 0.92-1.68; 4 studies; low certainty). The OSA-DR association is sensitive to the direction of the framed exposure-outcome relationship, to confounder adjustment, and to severity classification. Substantial attenuation of the unadjusted Arm 1 signal after adjustment, together with the inverse or null Arm 2 pattern, indicates that previously reported pooled estimates were influenced by confounding and by directional misclassification. Polysomnography-confirmed prospective cohorts with uniform DR grading and individual-participant-level adjustment for body mass index, diabetes duration, and metabolic comorbidities are needed to clarify the direction and magnitude of the relationship.
To evaluate the association of HbA1c level at the time of atrial fibrillation (AF) diagnosis with adverse outcomes (death, ischemic stroke (IS), myocardial infarction (MI), bleeding) in an unselected nationwide cohort of patients with AF and diabetes mellitus (DM). The retrospective FinACAF registry study covered all patients with incident AF in Finland between 2010 and 2017. Outcomes were analyzed using HRs and sHRs (hazard ratios and subdistribution hazard ratios), with HbA1c modelled both categorically and continuously. Among 157 658 patients with incident AF, DM was present in 23% (n = 35 872). Baseline HbA1c was available in 49% (17 519) of DM patients. DM was associated with increased hazards of all evaluated outcomes. Elevated HbA1c in categorical analyses was associated with progressively increased adjusted HRs and sHRs, with highest ratios seen in HbA1c > 63 mmol/mol for death (HR 1.56, 95% CI 1.45-1.68), IS (sHR 1.38 95% CI 1.20-1.59), and MI (sHR 1.70 95% CI 1.48-1.94), when compared to patients without DM. In continuous analyses, higher HbA1c levels were associated with increasing hazards for mortality, IS, and MI. Bleeding hazards remained stable across the HbA1c spectrum. Higher baseline HbA1c levels were associated with progressively increased hazards of mortality, IS, and MI in patients with incident AF and DM.
Phenylketonuria and type 1 diabetes are lifelong metabolic disorders requiring complex and potentially conflicting nutritional strategies. Their coexistence is rare, yet management may become particularly challenging during transition from pediatric to adult care. We describe the case of a young adult with phenylketonuria who developed type 1 diabetes. A 27-year-old man with longstanding phenylketonuria was referred to an adult metabolic-diabetes center after the diagnosis of type 1 diabetes. Clinical, biochemical, nutritional, and continuous glucose monitoring data were reviewed. The intervention included structured therapeutic education, transition from fixed insulin doses to a dynamic regimen based on carbohydrate counting, and revision of medical nutrition therapy using phenylketonuria-adapted low-protein foods and sugar-free phenylalanine-free amino acid supplements. At diagnosis, HbA1c was 11.5%, with markedly reduced C-peptide levels and high titer anti-GAD antibodies. Initial diabetes management was associated with poor adherence to the phenylketonuria diet, increased intake of conventional protein sources, and elevated phenylalanine levels. After individualized insulin titration and nutritional intervention, HbA1c improved from 11.5% to 7.8%, phenylalanine levels decreased from 842 to 705 μmol/L, insulin requirement declined from 0.55 to 0.3 IU/kg/day, and continuous glucose monitoring showed improved glycemic control without increased hypoglycemia. The Glycemia Risk Index improved from high-risk Zone E to low-intermediate-risk Zone B. This case highlights the need for personalized multidisciplinary care integrating continuous glucose monitoring, carbohydrate counting, and phenylketonuria specific nutrition to optimize both metabolic conditions.
Limited studies explored the association between ceramides and the risk of type 2 diabetes mellitus (T2DM). We aimed to investigated whether plasma ceramides and their ratios to Cer(d18:1/16:0) would be associated with T2DM in Chinese adult residents. This investigation was designed as a matched case-control study nested within a community-based longitudinal cohort in Suzhou, China. Plasma concentrations of eight ceramides (C16-C24) were measured quantitatively in 234 cases and 468 matched controls using high-throughput targeted lipidomics. Conditional logistic regression models were used to estimate odds ratios (ORs). We assessed the improvements in risk discrimination by net reclassification improvement (NRI) and integrated discrimination improvement (IDI). Seven ceramides (d18:1/16:0, d18:1/18:0, d18:1/20:0, d18:1/22:0, d18:1/22:1, d18:1/24:0, d18:1/24:1) were positively associated with incident T2DM. Among them, Cer(d18:1/24:0) showed the strongest association with increased T2DM risk (OR = 2.17 (95% CI: 1.29,3.66, P-trend < 0.05). Additionally, the ratios of Cer(d18:1/18:0)/Cer(d18:1/16:0) and Cer(d18:1/20:0)/Cer(d18:1/16:0) were significantly associated with T2DM risk, and adjusted ORs for the highest vs. lowest quartiles were 2.11 (95% CI: 1.27,3.51), and 1.69 (95% CI: 1.04,2.76), respectively (all P-trend < 0.05). The addition of individual ceramides or ceramide ratios to conventional risk factors significantly improved the discrimination and risk reclassification (all P < 0.05). Distinct plasma ceramides are associated with the T2DM risk and Cer(d18:1/24:0) serves as the strongest predictive marker. Moreover, the ratios of Cer(d18:1/18:0)/Cer(d18:1/16:0) and Cer(d18:1/20:0)/Cer(d18:1/16:0) are also particularly robust independent predictors of incident T2DM. Ceramides and their ratios can be used to identify high-risk patients with T2DM, providing targets for the primary and secondary prevention of T2DM.