This review is intended to highlight the need for non-invasive and earlier therapies for diabetic retinal disease (DRD), one of the most common complications of diabetes, with a high and increasing socioeconomic burden. Due to the growing evidence regarding the key role of neurodegeneration in the earliest stages of the disease and the underlying pathophysiological mechanisms, the relevance of evaluating the potential efficacy of neuroprotective therapies is emphasized. More specifically, the review addresses the current state of a promising neuroprotective approach based on the inhibition of the enzyme dipeptidyl peptidase-4 (DPP-4) using specific inhibitors administered via eyedrops, which allow direct retinal action on the neurovascular unit. The review discusses the main preclinical findings of a therapeutic strategy based on one DPP-4 inhibitor, sitagliptin, against early DRD in different experimental animal models and in vitro studies. In summary, sitagliptin eyedrops exhibit neuroprotective, anti-inflammatory, and antioxidant properties while reducing glial activation, hyperpermeability of the blood-retinal barrier, and the formation of acellular capillaries, leading to a functional improvement of the diabetic retina. However, as sitagliptin efficacy has only been evaluated at the preclinical level, clinical studies are needed to validate the translational applicability and long-term efficacy of topical administration not only of sitagliptin but also of other DPP-4 inhibitors for treating retinal diseases in which neurodegeneration plays a pathogenic role.

Diabetic kidney disease (DKD) is a primary cause of end-stage renal disease (ESRD), and while ferroptosis is known to contribute to DKD pathogenesis, the regulatory role of the NLRP3 inflammasome in this process remains elusive. To address this research gap, we explored whether NLRP3 inhibition alleviates DKD by suppressing ferroptosis using streptozotocin-induced diabetic wild-type and NLRP3-knockout C57BL/6 mice, alongside high-glucose-cultured (30 mM) human renal tubular epithelial (HK-2) cells with or without siNLRP3 transfection. Inflammatory cytokines (IL-6, TNF-α, and IL-1β) were measured using an ELISA; oxidative stress markers (CSSG, MDA, GSH, and ROS) and the iron ion content via colorimetric assays; mitochondrial morphology by transmission electron microscopy (TEM); and ferroptosis-related proteins (ACSL4, COX2, and GPX4) through Western blotting. Our findings demonstrate that NLRP3-knockout diabetic mice displayed markedly reduced urinary albumin excretion and serum creatinine levels (p < 0.01) compared with wild-type diabetic controls, concurrent with suppressed renal iron overload and ferroptosis, diminished inflammatory cytokine levels, and attenuated oxidative stress. Pathological assessments further revealed ameliorated renal fibrosis and preserved mitochondrial ultrastructure in NLRP3-deficient mice. In vitro, siNLRP3 transfection abrogated high-glucose-induced inflammation, oxidative stress, and ferroptosis in HK-2 cells, effects that were reversed by the ferroptosis inducer erastin (p < 0.01). Mechanistically, NLRP3 deficiency was associated with upregulated GPX4 expression and downregulated ACSL4 and COX2 expression. Collectively, these results indicate that inhibition of the NLRP3 inflammasome mitigates DKD progression by suppressing ferroptosis, underscoring its translational potential as a therapeutic target for this condition.

The current literature indicates that type 2 diabetes (T2DM) significantly increases the risk of cancer, including pancreatic cancer (PC). While metformin's primary role is the management of T2DM, its utility extends to systemic anti-cancer effects against various cancers. Nevertheless, its impact appears limited to risk reduction, as its efficacy as a primary or adjuvant treatment for established cancer remains unproven in clinical settings. This meta-analysis aimed to evaluate the association between metformin use-both as monotherapy and in combination with other antidiabetic drugs (ADs)-and the risk of PC. We synthesized data from 16 observational studies identified through PubMed, Cochrane Library, and Clinical Trials using the Population, Intervention, Comparison, Outcomes, and Study Type (PICOT) framework. The data were analyzed using Cochrane Review Manager software 5.4, with results reported as the relative risk (RR) and 95% confidence interval (95% CI) for each comparative group; statistical significance was defined as p-value < 0.05. Our findings indicate that metformin demonstrated a significant reduction in overall PC risk when compared to the pooled group of alternative ADs. Furthermore, metformin significantly lowers PC risk compared to sulfonylureas (SUs), alpha-glucosidase inhibitors (AGIs), and insulin. Conversely, metformin use was associated with a markedly elevated PC risk relative to thiazolidinediones (TZDs) and DPP-4 inhibitors (DPP4i). Considering metformin monotherapy vs. its combination with other ADs, we found that metformin lowered the risk of PC compared to its combination with SUs and AGIs but elevated the PC risk relative to its combination with TZDs and DPP4i. To conclude, these results suggest that metformin may protect patients with T2DM from PC development. However, individual PC risk and diabetes compliance should be taken into account when deciding whether to add an additional AD(s) to metformin therapy.

Diabetic foot infection (DFI) is a serious complication of diabetes mellitus associated with chronic inflammation, impaired wound healing, endothelial dysfunction, and oxidative stress. Sirtuin (SIRT) signaling and the apelinergic system have been implicated in these processes. This study aimed to evaluate serum SIRT1, SIRT3, apelin, and elabela (ELA) levels in patients with DFI and to examine their cross-sectional associations with clinical indicators, inflammatory markers, osteomyelitis, and glycemic control.

This cross-sectional study included 47 patients with DFI and 42 healthy controls. Serum biomarker levels were measured using enzyme-linked immunosorbent assay (ELISA). Clinical and laboratory data, including the infection component of the PEDIS classification, were recorded. Group comparisons, Spearman correlation analyses, receiver operating characteristic (ROC) curve analysis, and logistic regression were performed.

Patients with DFI exhibited higher inflammatory and glycemic markers and lower hemoglobin and lipid levels compared with controls (p < 0.05). Serum SIRT1, SIRT3, apelin, and ELA levels were significantly lower in the DFI group and showed inverse correlations with HbA1c, PEDIS stage, disease duration, osteomyelitis, and inflammatory markers. Among these biomarkers, SIRT1 showed the highest discriminative ability within this cohort (AUC = 0.820). In an exploratory multivariable model, age and SIRT1 were independently associated with the presence of DFI.

Serum SIRT1, SIRT3, apelin, and ELA levels were lower in patients with DFI and were associated with clinical and biochemical indicators of disease burden. Among these biomarkers, SIRT1 demonstrated the strongest discriminative ability within this cohort. These findings suggest that sirtuin signaling and the apelinergic system may be relevant in the biological context of DFI; however, they should be interpreted cautiously. The observed differences may reflect not only DFI but also underlying diabetes, glycemic burden, age, and systemic inflammation. Further prospective studies including appropriate diabetic comparator groups are required to clarify the clinical relevance and potential utility of these biomarkers.

Diabetes mellitus (DM) is associated with multiple systemic complications, yet its effects on respiratory muscle structure remain insufficiently characterized. This study aimed to evaluate diaphragmatic morphology in patients with type 2 DM and to determine whether glycemic control is associated with diaphragmatic thickness.

A total of 120 participants were enrolled, including 60 patients with type 2 DM and 60 healthy controls. Demographic, biochemical, and diaphragmatic ultrasound parameters were assessed, including right and left diaphragm thickness (DT) during inspiration and expiration, diaphragmatic excursion (DE), and costophrenic angle (CPA). All patients with DM underwent electromyography for evaluation of peripheral neuropathy. Diabetic participants were further stratified according to glycemic control using an HbA1c threshold of 7%. Correlation analyses and multivariable linear regression models adjusted for age and body mass index (BMI) were performed to examine the association between HbA1c and diaphragmatic parameters.

Compared with controls, patients with DM were older and had higher fasting glucose levels but lower total cholesterol, whereas BMI and other biochemical parameters were comparable. Peripheral neuropathy was identified in 28.3% of patients with DM, but was not associated with significant differences in DT, DE, or CPA. In the three-group analysis, right and left DT measured during both inspiration and expiration differed significantly among well-controlled DM, poorly controlled DM, and control groups, whereas DE and CPA remained similar. Within the DM cohort, higher HbA1c levels were significantly associated with lower right and left DT values. These inverse associations remained independent after adjustment for age and BMI, while no independent associations were observed between HbA1c and either DE or CPA.

Poorer glycemic control was associated with reduced diaphragmatic thickness in patients with T2DM. Ultrasonographic assessment may offer a non-invasive approach for detecting early respiratory muscle involvement, although its clinical and functional relevance should be validated in future prospective studies.

Metabolic dysfunction-associated steatotic liver disease (MASLD) is strongly associated with metabolic abnormalities, shares pathophysiological pathways with metabolic syndrome, and has become a leading cause of chronic liver disease in industrialized nations. In the absence of approved pharmacological treatments and due to its high risk of progression to advanced fibrosis, MASLD represents a significant clinical challenge. Incretin-based therapies, originally developed for the treatment of type 2 diabetes mellitus and obesity, have recently gained attention as promising therapeutic strategies in hepatology. Among them, GLP-1 receptor agonists have shown efficacy in reducing hepatic steatosis, inflammation, and fibrosis-related biomarkers, primarily through weight loss and enhanced insulin sensitivity. Dual agonists targeting both GLP-1 and GIP receptors, such as tirzepatide, have demonstrated superior outcomes in improving hepatic and metabolic parameters. Emerging agents like cotadutide (a GLP-1/glucagon receptor agonist) and retatrutide (a GLP-1/GIP/glucagon triagonist) represent a novel therapeutic frontier, with early clinical data indicating potent hepatoprotective effects and favorable metabolic remodeling. This narrative review examines the hepatoprotective potential of incretin-based therapies, highlighting how targeted intervention on the underlying metabolic dysfunction may lead to significant improvements in MASLD. These therapies may also exert beneficial effects on fibrosis progression; however, the currently available evidence remains limited.

Background and Objectives: Diabetic peripheral neuropathy (DPN) is a common and debilitating complication of obesity and type 2 diabetes (T2D) affecting up to 50% of patients with long-standing disease. While chronic hyperglycemia plays a central role in its pathogenesis, intensive glycemic control provides only partial protection, suggesting the involvement of additional metabolic pathways. The primary objective of this systematic review was to evaluate the role of lipid metabolism disturbances and advanced lipidomic alterations in the development and progression of DPN in patients with obesity and T2D. Secondary objectives included identifying specific lipid species associated with DPN and exploring their potential pathophysiological and clinical implications. Methods: This systematic review included 8 studies that met the inclusion criteria and was conducted according to PRISMA guidelines and registered in PROSPERO/2026/CRD420261288920. Study quality was assessed using the Newcastle-Ottawa Scale. Results: Large population-based cohorts reported a consistent association between hypertriglyceridemia and DPN prevalence, with triglyceride levels >204 mg/dL associated with an approximately 40% increased risk. Lipidomic analysis revealed alterations in acylcarnitine, sphingolipids, and phospholipids. However, the evidence remains limited and heterogeneous, and neuropathy-specific outcomes were insufficiently evaluated in interventional studies. Conclusions: Lipid metabolism disturbances, particularly hypertriglyceridemia and specific lipidomic alterations, may contribute to DPN beyond the effects of hyperglycemia. Although not yet clinically actionable, lipidomic alterations may represent promising future biomarkers and therapeutic targets in DPN. However, the current evidence is limited by heterogeneity and predominantly observational designs. Further well-designed longitudinal and interventional studies are needed to clarify causal relationships and clinical relevance.

Background: Retinal and optic nerve disorders remain major causes of visual morbidity worldwide. Ocular fundus flavoprotein fluorescence (FPF) imaging has emerged as a potential noninvasive biomarker of mitochondrial dysfunction for earlier detection and evaluation of disease severity. Methods: We conducted a Systematic Scoping Review of the diagnostic and correlational utility of quantitative FPF parameters in retinal and optic nerve diseases compared with healthy controls. Following PRISMA-ScR guidelines, we searched MEDLINE, Web of Science, Scopus, and CENTRAL for peer-reviewed human studies available online before 31 December 2025. Results: Seventeen studies were included, encompassing 1914 eyes and 1339 participants, and were predominantly cross-sectional. In healthy eyes, mean macular and optic nerve head FPF intensity were reported as 24.1 ± 12.2 gsu and 30.6 ± 14.6 gsu, respectively. Higher signals were reported in several disorders, including diabetes mellitus (76.0 [67.0-92.0] gsu), neovascular age-related macular degeneration (67.47 ± 17.77 gsu), and retinitis pigmentosa (50.5 ± 12.2 gsu). However, lower, unchanged, or stage-dependent signals were also observed within the same disease categories. Interpretation across studies was limited by substantial heterogeneity in patient selection, disease definitions, imaging protocols, control groups, and FPF outcome metrics. The precise cellular and sublayer origin of the detected signal also remains challenging to determine. Conclusions: Ocular fundus FPF imaging provides promising metabolic insight into retinal and optic nerve diseases. However, current evidence remains heterogeneous and largely cross-sectional, limiting clinical interpretability and generalizability. Longitudinal studies, technical standardization, and multimodal integration are needed to define reproducible disease-specific FPF profiles and improve translational applicability.

Background: The ankle-brachial index (ABI) is a popular method for evaluating peripheral artery disease (PAD). However, it is unreliable in patients with diabetes mellitus (DM), particularly in cases of media arterial calcification (MAC), where falsely elevated or unreliable values may be produced. The toe-brachial index (TBI) is therefore recommended in such cases, but has its limitations. The tissue optical perfusion pressure (TOPP) method is another automated diagnostic protocol combining oscillometric ABI measurement (oABI) and photo-plethysmographic pulse-wave assessment using the pulse wave index (PWI). The study evaluated TOPP-derived parameters in diabetic patients with or without MAC, in comparison with established functional vascular examinations. Methods: PAD patients with DM presenting in our outpatient clinic were enrolled prospectively from January to August 2024. Patients with peripheral bypasses or deemed unsuitable for the TOPP method were excluded. All patients received an ABI, TBI and TOPP measurement. Results: A total of 107 patients with DM were included in the present study. 38 patients presented with MAC and 69 patients without. The majority were male. Most patients presented with claudication (20 Fontaine stage IIa, 30 stage IIb), 9 presented with rest pain (Fontaine stage III), and 31 with wounds (Fontaine stage IV). 17 patients were free of symptoms (Fontaine stage I). The two parameters of the TOPP method, oABI and PWI, both correlated with the TBI and ABI. In patients with MAC, the oABI did not correlate with any other measurement, but the PWI did weakly correlate with the TBI. MAC is an important factor in influencing measurement accuracy. Despite their limitations, the TBI showed a significant correlation to the clinical symptoms (correlation coefficient = -0.387, p < 0.001). Conclusions: In patients without MAC, oABI and PWI correlated with ABI and TBI. TBI was the most reliable parameter in those with MAC. PWI correlated with TBI, but the correlation was weak. TBI should not be replaced by PWI. PWI may provide complementary information in a diagnostic protocol. oABI did not correlate with clinical symptom severity in DM patients, independently of the presence of MAC, and is unsuitable as a stand-alone parameter. A combination of TBI and TOPP-derived parameters may help to assess the severity of peripheral artery disease in diabetic patients with MAC. Larger multicentre studies are required.

Objective: To investigate whether gestational diabetes mellitus (GDM), including insulin-treated GDM, affects cerebroplacental ratio (CPR) values in monochorionic diamniotic (MCDA) twin pregnancies. Methods: This retrospective single-center cohort study included a total of 262 MCDA twin pregnancies managed at a tertiary referral center, comprising pregnancies without GDM (n = 120), with diet-controlled GDM (n = 80), and with insulin-treated GDM (n = 62). Doppler ultrasound examinations were performed at three gestational time points between 24 and 36 weeks of gestation. CPR, umbilical artery pulsatility index (UA-PI), and middle cerebral artery pulsatility index (MCA-PI) were compared longitudinally between groups. Doppler indices were compared between groups without adjustment for baseline differences such as BMI and parity Results: Maternal body mass index was significantly higher in pregnancies complicated by GDM, particularly in those requiring insulin therapy (p < 0.001). Estimated fetal weight was higher in the insulin-treated GDM group at mid-gestation (28-32 weeks; p = 0.01). However, CPR values remained within normal ranges throughout all screening points across all three groups. No relevant differences in UA-PI, MCA-PI, gestational age at delivery, Apgar scores, or umbilical cord pH were observed between groups. Conclusions: In MCDA twin pregnancies, gestational diabetes-regardless of insulin treatment-does not appear to significantly influence cerebroplacental ratio values throughout gestation. No statistically significant differences in CPR values were observed between groups. No statistically significant differences in CPR values were detected between groups. However, given the exploratory design and lack of adjustment for confounders, subtle effects cannot be excluded. The clinical utility of CPR in this population requires further investigation.