Chronic exposure to reactive carbonyl species such as glyoxal and methylglyoxal, along with hydroxyl radicals (•OH), leads to glycative and oxidative damage, contributing to insulin resistance and diabetic complications. Pyridoxamine (PM) is known to counteract these effects, but its potential synergy with mannitol (MN), a hydroxyl radical scavenger, remains unexplored. This study investigates the combined efficacy of MN and PM in preventing glycation and oxidative damage in vitro. Calf thymus DNA was subjected to glycation using 10 mM glyoxal, oxidation via the Fenton reaction, and sequential glycoxidation (glycation followed by oxidation). The inhibitory effects of MN, PM, and their combination were assessed using NBT reduction for early glycation, GK-ribose for AGEs, TBARS for hydroxyl radicals, and spectroscopic analyses for AGEs formation. A clinical study also examined autoantibody prevalence in diabetes and diabetic retinopathy (DR). Results showed that glycoxidated DNA exhibited structural alterations, with MN and PM individually reducing ketoamine content. Their combination further enhanced glycation and glycoxidation inhibition. Additionally, MN-PM co-administration synergistically reduced AGEs and hydroxyl radicals. Autoantibody levels were elevated in diabetes and DR. These findings suggest PM-MN co-administration as a promising strategy to mitigate diabetic complications.

This study endeavors to unveil the association between the Metabolic Score for Insulin Resistance (METS-IR) and stroke among adults utilizing data of the National Health and Nutrition Examination Survey (NHANES) and the China Health and Retirement Longitudinal Study (CHARLS), and whether oxidative stress (OS) mediates their association.

Our study cohort comprised 101,316 individuals from NHANES and 17,708 individuals from CHARLS. The intricate relationships among the METS-IR, stroke, and OS biomarkers were evaluated via logistic regression, restricted cubic splines (RCS), as well as mediation analysis.

The final analysis included 22,542 American and 9521 Chinese participants, among whom 844 and 887 were diagnosed with stroke, respectively. Regression analysis indicated a positive association of METS-IR with stroke [NHANES: OR = 1.01, 95 % CI (1.01, 1.02), p < 0.001; CHARLS: OR = 1.02, 95 % CI (1.02, 1.03), p < 0.001], with higher METS-IR quartiles being associated with elevated stroke incidence [NHANES: OR = 1.39, 95 % CI (1.11, 1.73), p = 0.004; CHARLS: OR = 1.74, 95 % CI (1.39, 2.17), p < 0.001]. Participants with elevated METS-IR and serum uric acid (SUA) exhibited the greatest probability of stroke. Mediation analysis proved that OS partially mediated this association [Mediation effect: NHANES β = -8.45e-5, 95 % CI (-1.41e-4, -4.01e-5), p < 0.001; CHARLS β = -4.02e-5, 95 % CI (-8.14e-5, -7.76e-6), p = 0.012].

The METS-IR was positively associated with stroke in NHANES and CHARLS cohorts, and OS partially mediated this association.

Glycaemic therapy in type 1 diabetes (T1D) is focused on insulin, with the majority of studies investigating different insulin preparations, delivery devices and dosing accuracy methods. While insulin deficiency is the key mechanism for hyperglycaemia in T1D, individuals with this condition can also develop insulin resistance (IR), making optimisation of glycaemia more challenging. Importantly, IR in T1D increases the risk of both microvascular and macrovascular complications; yet, it is rarely targeted in routine clinical care. In this narrative review, we briefly discuss the mechanistic pathways for diabetes complications in individuals with T1D, emphasising the adverse role of IR. We subsequently cover the use of adjunctive glycaemic therapies for improving the metabolic profile in T1D, focusing on therapies that have possible or definite cardiovascular or renal protective properties in individuals with type 2 diabetes. These include metformin and agents in the thiazolidinedione, Sodium-Glucose Cotransporter-2 inhibitor (SGLT2i) and Glucagon-Like Peptide-1 Receptor Agonists (GLP-1RA) groups. In addition to reviewing the role of these agents in improving metabolic parameters, we address their potential vascular and renal protective effects in individuals with T1D. We suggest a pragmatic approach for using these agents in T1D, based on current knowledge of their benefits and risks, while also highlighting gaps in knowledge and areas that require further research. It is hoped that the review raises awareness of the role of adjunctive therapies in T1D and offers healthcare professionals simple guidance on using such agents for the management of high-risk individuals with T1D.

Triglyceride- glucose (TyG) index, a marker of insulin resistance, has been shown to be associated with the incidence of cardiometabolic diseases including hypertension. However, the prognostic role of TyG index is unknown. Hence, we aim to determine the association of TyG index with major adverse cardiovascular events (MACE) in hypertensive patients.

Systematic searching was conducted on 3 databases up till November 2024. We included studies with hypertensive patients despite their comorbidities. Outcome measured is MACE and its individual components. Random effect model meta-analysis is done to pool the results with similar reference point.

Twenty observational studies with a total of 451,455 patients of 40 - 70 years old are included. Meta-analysis result shows that higher TyG index is associated with a statistically significant increased risk of MACE (HR 1.90, CI: 1.41 - 2.57, I2 88 %), myocardial infarction (HR 1.55, CI: 1.27 - 1.88, I2 0 %), stroke (HR 1.84, CI: 1.41 - 2.39, I2 62 %), all- cause mortality (HR 1.86, CI: 1.70 - 2.03, I2 0 %) and cardiovascular mortality (HR 1.08, CI: 1.04 - 1.11, I2 0 %). Subgroups of older and younger population, male and female gender, diabetic and non- diabetic population, and higher BMI patients retains the statistically significant risk of MACE (p < 0.05). U- shaped phenomena of TyG index is also demonstrated with the risk of all- cause mortality.

TyG index is a reliable prognostic marker of MACE in hypertensive patients and can be utilized in population despite their age, diabetic status, and gender.

Diabetic retinopathy (DR), the prevalence of which continues to rise, is one of the most common causes of vision loss worldwide. Experimental and clinical research in recent years has contributed to a better understanding of the pathogenesis of DR, which is complex and results from many interrelated processes leading to abnormal permeability and occlusion of the retinal vasculature, with ischemia and subsequent neovascularization. According to the absence or presence of neovascularization, DR is divided into two main forms: nonproliferative and proliferative DR. From nonproliferative to proliferative disease, diabetic macular edema (DME) can develop anywhere along the spectrum. As the majority of diabetics have no ophthalmologic symptoms, screening plays an important role in preventing the development of retinal disease. Specific treatment options beyond metabolic risk factor control, including intravitreal administration of anti-vascular endothelial growth factor (VEGF) agents or corticosteroids, laser photocoagulation, and vitreous surgery, are effective approaches for ocular diabetic complications.

Diabetes mellitus, a most common endocrine disorder of glucose metabolism, has become a global epidemic and poses a serious public health threat with an increased socio-economic burden. Escalating incidence of diabetes is correlated with changes in lifestyle and food habits that cause gut microbiome dysbiosis and β-cells damage, which can be addressed with dietary interventions containing probiotics. Hence, the search for probiotics of human origin with anti-diabetic, anti-AGE, and anti-ACE potentials has gained renewed interest for the effective management of diabetes and its associated complications. The present study used an alloxan (AXN)-induced diabetic rat model to investigate the effects of potential probiotic Lacticaseibacillus casei MKU1, Lactiplantibacillus pentosus MKU3, and Lactiplantibacillus plantarum MKU7 administration individually on physiochemical parameters related to diabetic pathogenesis. Experimental animals were randomly allotted into six groups viz. NCG (control), DCG (AXN), DGM (metformin), DGP1 (MKU1), DGP2 (MKU3), and DGP3 (MKU7), and biochemical data like serum glucose, insulin, AngII, ACE, HbA1c, and TNF-α levels were measured until 90 days. Our results suggest that oral administration with MKU1, MKU3, or MKU7 significantly improved serum insulin levels, glycemic control, glucose tolerance, and body weight. Additionally, β-cell mass was increased by preserving islet integrity in Lactobacillus-treated diabetic rats, whereas TNF-α (~40%), AngII (~30%), and ACE levels (~50%) were strongly inhibited and enhanced sIgA production (5.8 folds) abundantly. Furthermore, Lactobacillus administration positively influenced the gut microbiome with a significant increase in the abundance of Lactobacillus species and the beneficial Bacteroides uniformis and Bacteroides fragilis, while decreased the pathogenic Proteus vulgaris and Parabacteroides distasonis. Among the probiotic treatment groups, L. pentosus MKU3 performed greatly in almost all parameters, indicating its potential use for alleviating diabetes-associated complications.

A rapid and sensitive ultra-high-performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS) method was developed and validated for epalrestat detection in human plasma.

A triple quadrupole tandem mass spectrometer equipped with an electrospray ionization (ESI) source was used to quantify epalrestat and the internal standard epalrestat-d5 in the negative ion mode using multiple reaction monitoring (MRM). After acetonitrile-mediated protein precipitation, chromatographic separation was achieved using a reversed-phase C18 column (ACQUITY UPLC BEH, 2.1 × 50 mm, 1.7 μm; Waters Corp) with acetonitrile and 2 mM ammonium acetate in water as the mobile phase through gradient elution.

The retention time of epalrestat was 0.92 min and the entire run time was only 2.00 min. The calibration curve was linear in the range 10.0-8.00 × 103 ng/mL (r ≥ 0.99). The within-run and between-run relative standard deviations (RSDs) were < 9.3%. The within-run and between-run relative errors (REs) ranged -8.4-4.2%. No significant matrix effects were observed and the recovery rate was high. The method was fully validated, including reinjection reproducibility in human plasma, and was successfully applied in a pharmacokinetic study, in which 100% incurred sample reanalysis met the criteria.

Previous studies reporting lower skeletal muscle mitochondrial function in type 1 diabetes did not account for cardiorespiratory fitness, a key confounder when assessing mitochondrial function. We hypothesised that, compared with healthy individuals, muscle mitochondrial phenotypic differences would be abolished in individuals with type 1 diabetes when matched for age, sex, BMI and maximal oxygen uptake (V ˙ O 2max ).

Seventeen individuals with type 1 diabetes and seventeen healthy control individuals matched for age, sex, BMI andV ˙ O 2max participated and underwent a muscle biopsy from the vastus lateralis. Mitochondrial respiration was assessed by high-resolution respirometry, and mitochondrial density and morphology were assessed by transmission electron microscopy.

V ˙ O 2max (individuals with type 1 diabetes 40±10 kg-1 min-1; control individuals 41±8 ml kg-1 min-1; p=0.51) and mitochondrial oxidative phosphorylation capacity (individuals with type 1 diabetes 101±35 [pmol O2] s-1 mg-1; control individuals 99±23 [pmol O2] s-1 mg-1, p=0.82) did not differ between groups. Both intermyofibrillar (individuals with type 1 diabetes 6.07±2.16%; control individuals 6.01±1.11%; p=0.92) and subsarcolemmal (individuals with type 1 diabetes 18.70±8.16%; control individuals 19.29±7.36%; p=0.83) mitochondrial densities were not different between groups. Mitochondrial respiration normalised by density did not differ between groups. However, individuals with type 1 diabetes and higher HbA1c displayed lower rates of mitochondrial respiration than those with lower HbA1c, whereas those with higher BMI displayed lower mitochondrial densities than those with lower BMI.

Collectively, our study demonstrates that when matched for age, sex, BMI andV ˙ O 2max , maximal muscle mitochondrial respiration and morphology in people with type 1 diabetes are not impaired. These findings highlight the importance of habitual exercise, optimal glucose management and a healthy BMI in maintaining mitochondrial health in individuals with type 1 diabetes.

Cardiac diastolic dysfunction is a hallmark of diabetic cardiomyopathy (DCM), particularly in postmenopausal women where estrogen deficiency exacerbates cardiac remodeling. This study investigated the roles of NLRP3 inflammasome activation and cardiac mast cell (CMC) behavior in diabetic ovariectomized (OVX) rat models. Female Wistar rats were divided into five groups: sham-operated, OVX, diabetic (Sham-DM), OVX-diabetic (OVX-DM), and OVX-DM treated with the NLRP3 inhibitor MCC950. Diabetes was induced using a high-calorie quick fat diet (13.8% crude fat, 24.35% crude protein, 25% sucrose; 406.80 kcal/100 g) followed by a single intraperitoneal injection of streptozotocin (30 mg/kg). MCC950 (10 mg/kg BW, intraperitoneally) was administered daily for 4 weeks. Echocardiography revealed significant diastolic dysfunction in OVX-DM rats, with increased left ventricular internal diameter (LVIDd) and reduced mitral valve E/A ratio, while MCC950 treatment partially restored diastolic function (p < 0.05). Masson's trichrome staining showed increased myocardial fibrosis in OVX-DM rats (2.59 ± 0.20%) compared to Sham-DM (1.94 ± 0.16%, p < 0.05), which was reduced with MCC950 treatment (0.88 ± 0.13%, p < 0.05). Western blot analysis demonstrated elevated expression of NLRP3, cleaved caspase-1, IL-1β, and GSDMD-N in OVX-DM hearts. MCC950 significantly reduced cleaved caspase-1, IL-1β, and GSDMD-N expression without altering NLRP3 protein levels. Additionally, mast cell degranulation was markedly increased in OVX-DM rats (62.14%) compared to controls (P < 0.05) and was attenuated by MCC950 (31.06%, P < 0.05). These findings suggest that NLRP3 inflammasome activation under conditions of estrogen deficiency and diabetes contributes to myocardial pyroptosis and mast cell degranulation, driving cardiac remodeling in postmenopausal DCM. Targeting NLRP3 pathways may provide an effective therapeutic strategy to mitigate diastolic dysfunction, fibrosis, and inflammation in diabetic hearts.

Atherosclerosis (AS) remains a leading cause of cardiovascular disease and mortality globally. This chronic condition is characterized by inflammation, lipid accumulation, and the deposition of cellular components within arterial walls. Emerging evidence has highlighted the multifaceted therapeutic potential of short-chain fatty acids (SCFAs) in mitigating AS progression. SCFAs have demonstrated anti-inflammatory properties and the ability to regulate immune responses, metabolic pathways, vascular integrity, and intestinal barrier function in animal models of AS. Consequently, SCFAs have garnered significant attention as a promising approach for the prevention and treatment of AS. However, further clinical trials and studies are necessary to fully elucidate the underlying mechanisms and effects of SCFAs. Additionally, different types of SCFAs may exert distinct impacts, necessitating more in-depth investigation into their specific roles and mechanisms. This review provides an overview of the diverse cellular mechanisms contributing to AS formation, as well as a discussion of the significance of SCFAs in AS pathogenesis and their multifaceted therapeutic potential. Nonetheless, additional research is warranted to comprehensively understand and harness the potential of various SCFAs in the context of AS.

Negative pressure wound therapy (NPWT) is widely recognized for its efficacy in treating diabetic wounds, but the mechanisms involved in the wound healing process remain unclear. By examining changes in blood cytokine levels as molecular signaling precursors, we aim to provide a comprehensive cytokine profile to support adjunctive therapy research and clinical applications. A diabetic mouse wound model was established to compare cytokine profiles between NPWT-treated and standard dressing groups, identifying key signaling candidates that may facilitate wound healing. By integrating normal mouse data with large-scale cytokine analysis, we developed a time-stratified NPWT approach to track acute-phase cytokine fluctuations in diabetic conditions. NPWT did not significantly enhance coagulation-related cytokine expression but effectively reduced inflammation, albeit with a delayed regulatory effect compared to wild-type mice. A one-sided binomial test revealed that NPWT advanced the cytokine expression peak from 16 to 2 h, partially restoring the early healing pattern seen in normal mice and suggesting its potential role in modulating early-stage wound repair. These findings provide novel insights into early cytokine regulation during wound healing and highlight the potential of NPWT to inform therapeutic strategies. This refined monitoring approach may contribute to improved clinical decision-making and support enhanced wound management in diabetic patients.

Diabetic retinopathy (DR) is a leading cause of blindness among adults with diabetes. Glycated hemoglobin A1C (HbA1C) is a critical biomarker for long-term glycemic control and has been closely associated with the risk of developing DR. However, the relationship between HbA1C and DR remains complex and multifaceted, with limited research exploring the nonlinear aspects of this association. This study aims to investigate the nonlinear relationship between HbA1C and DR, providing insights into their association and informing clinical interventions.

Many studies have indicated that HbA1C is positively correlated with DR. However, although elevated HbA1C is common in patients with DR, its relationship with DR remains controversial. Our study aimed to investigate the nonlinear relationship between HbA1c and DR, thereby accurately elucidating their association and providing a basis for clinical interventions.

This study is the second analysis based on a cross-sectional studv. A total of 2,001 patients with type 2 Diabetes Mellitus (T2DM) visited the diabetic clinic in the Internal Medicine outpatient departments of two hospitals in southern Taiwan between April 2002 and November 2004 were included in this analysis. Demographic and clinical data were collected, and HbA1c levels were measured. The association between HbA1c and DR was analyzed using multivariate logistic regression, adjusting for potential confounders, and the potential nonlinear correlation was explored with a smooth curve fitting approach.

The fully-adjusted model showed that HbA1c positively correlated with DR (OR:1.13, 95%CI: 1.05-1.22). However, an inverted U-shaped association between them was observed by applying the smooth curve fitted method. The inflection point of HbA1c (9.4%) was calculated by utilizing the two-piecewise logistic regression model. In the subgroup analysis, the inverted U-shaped nonlinear correlation between HbA1c and DR was also found in age, sex and BMI.

HbA1C and DR have an inverted U-shaped relationship, with a peak at an HbA1C of 9.4% in the early phase of DR. After this peak, HbA1C decreases as DR increases. These results have crucial implications for DR patients. The findings also offer insights for public health policy, highlighting the necessity of regular screening and intervention for diabetic patients. Future research should further explore the mechanisms linking HbA1c to DR and consider individualized management strategies for different populations to effectively mitigate the burden of DR.

The precise pathogenic mechanism of long-term detrimental effects on mothers and infants resulting from gestational diabetes (GDM) remains unclear. This study aimed to examine the long-term detrimental consequences of GDM on mothers and newborns, particularly the impact of glucose concentration variations on vascular endothelial cells and its possible pathogenic mechanisms.

An analysis was conducted on the clinical data of 68 healthy pregnant women and 67 pregnant women diagnosed with GDM. Human umbilical vein endothelial cells (HUVECs) were obtained from six pairs of pregnant women for transcriptomic sequencing and analysis, which were concurrently analysed with existing databases. The study examined the effects of varying glucose concentrations on HUVECs, incorporating relevant biological experimental verifications, and assessed oxidative stress, inflammation, and the TGF-β signalling pathway.

Clinical data analysis indicated that in patients with gestational diabetes mellitus, early pregnancy hyperglycemia is significantly linked to adverse pregnancy outcomes, even when blood glucose levels are well-controlled. Transcriptomic sequencing revealed significant alterations in the gene expression of HUVECs under GDM conditions, highlighting enrichment in genes associated with metabolism, inflammation, oxidative stress, and diabetes signalling pathways. Cellular experiments indicated that a transition in glucose concentration from elevated to reduced levels can result in damage and dysfunction in HUVECs, elevate ROS levels, and activate the TGF-β signalling pathway. Additionally, injured HUVECs release CTGF through the TGF-β signalling pathway, influencing the extracellular matrix and surrounding cells.

The findings demonstrate that alterations in glucose concentration, particularly the shift from high to low levels, can lead to vascular endothelial cell dysfunction, increase ROS levels, and are associated with the TGF β/SMAD3 signalling pathway. Furthermore, compromised HUVECs can influence the microenvironment via their secretions, potentially jeopardising the health of both the mother and foetus.

People with type 1 diabetes (T1D) are usually considered to exclusively exhibit β-cell failure, but they frequently also feature insulin resistance. This review discusses the mechanisms, clinical features, and therapeutic relevance of insulin resistance by focusing mainly on human studies using gold-standard techniques (euglycemic-hyperinsulinemic clamp). In T1D, tissue-specific insulin resistance can develop early and sustain throughout disease progression. The underlying pathophysiology is complex, involving both metabolic- and autoimmune-related factors operating synergistically. Insulin treatment may play an important pathogenic role in predisposing individuals with T1D to insulin resistance. However, the established lifestyle-related risk factors and peripheral insulin administration inducing glucolipotoxicity, hyperinsulinemia, hyperglucagonemia, inflammation, mitochondrial abnormalities, and oxidative stress cannot always fully explain insulin resistance in T1D, suggesting a phenotype distinct from type 2 diabetes. The mutual interaction between insulin resistance and impaired endothelial function further contributes to diabetes-related complications. Insulin resistance should therefore be considered a treatment target in T1D. Aside from lifestyle modifications, continuous subcutaneous insulin infusion can ameliorate insulin resistance and hyperinsulinemia, thereby improving glucose toxicity compared with multiple injection insulin treatment. Among other concepts, metformin, pioglitazone, incretin-based drugs such as GLP-1 receptor agonists, sodium-glucose cotransporter inhibitors, and pramlintide can improve insulin resistance, either directly or indirectly. However, considering the current issues of high cost, side effects, limited efficacy, and their off-label status, these agents in people with T1D are not widely used in routine clinical care at present.

The hyperglycemic state in diabetes mellitus induces oxidative stress and inflammation, contributing to diabetic tissue damage and associated complications. Astaxanthin, a potent antioxidant carotenoid, has been investigated for its potential to prevent and manage diabetes across various species; however, its effect on client-owned dogs remains poorly studied. This study explored the impact of astaxanthin supplementation on canine diabetes mellitus using a proteomics approach. A total of 18 client-owned dogs were enrolled: 6 dogs with diabetes mellitus and 12 clinically healthy dogs. The diabetic dogs received their standard treatment regimen along with daily oral supplementation of 12 mg of astaxanthin (1.5-2.4 mg/kg) for 90 days. Plasma samples were collected at the beginning and end of the study period for proteomics analysis. After astaxanthin supplementation, significant alterations in the expression of proteins associated with the complement system, coagulation cascade, JAK-STAT signaling, and protein kinase C signaling (all of which contribute to inflammation and oxidative stress) were observed. Astaxanthin exhibited potential for reducing diabetes-associated complications, such as insulin resistance, vascular dysfunction, nephropathy, and cardiac issues, even though it did not affect clinical parameters (hematology, plasma biochemistry, blood glucose, and serum fructosamine). These findings suggest that astaxanthin may be a valuable complementary therapy for managing diabetes-related complications in canines.

To examine the effects of fluctuations in fasting blood glucose (FBG) levels on left ventricular function in patients with T2DM and coronary microcirculation dysfunction (CMD).

A total of 290 patients with T2DM who received glucose-lowering therapy during hospitalization and were subsequently followed up for 18 months at the First Affiliated Hospital of Harbin Medical University, were enrolled in this study. 135 were diagnosed with CMD and were assigned to the CMD group, whereas 155 patients without CMD were allocated to the non-CMD group. The fasting blood glucose coefficient of variation (FBG-CV) was calculated for all participants. The CMD group was further stratified into three subgroups based on their FBG-CV values: CMD1 (FBG-CV > 25%), CMD2 (FBG-CV 15% ~ 25%), and CMD3 (FBG-CV < 15%). The left ventricular function, assessed by left ventricular ejection fraction (LVEF) and the E/e' ratio, was compared within each group before and after the follow-up period. This study was registered in the Chinese Clinical Trial Register, ChiCTR-ORC-16009800.

After the end of follow-up, the E/e' ratio in CMD1 was significantly higher than that in CMD2 and CMD3 (14.35 vs 8.57; p < 0.01; 14.35 vs 6.61; p < 0.01), and the E/e' ratio in CMD2 was significantly higher than that in CMD3 (8.57 vs 6.61; p < 0.01). Compared to the baseline measurements, the E/e' ratio in CMD1 showed a significant increase after an average 17.8 months of follow up (14.35 vs 8.44; p < 0.001). We found elevated E/e' ratio was associated with an increased FBG-CV level (odds ratio [OR]: 2.571; 95% CI 1.819-3.634; p < 0.001). In multivariate logistic analysis, course of diabetes (OR:1.062; 1.016-1.11; P = 0.007) and CMD (OR:2.231; 1.303-3.819; P = 0.003), were significantly associated with elevated E/e' ratio, while oral stains drugs (OR = 0.412 95% CI 0.237-0.715; P = 0.002) and insulin injections (OR = 0.536 95% CI 0.311-0.924; P = 0.025) behaved as a protective factor.

Our study clarified the association between FBG-CV levels and the E/e' ratio in a prospective cohort study. In T2DM patients with CMD, FBG-CV > 25% may adversely affect left ventricular diastolic function, whereas an optimal FBG-CV is considered to be less than 15%.

Diabetic retinopathy (DR), a complication of type 2 diabetes mellitus (T2DM), is typically asymptomatic in its early stages. Diagnosis typically relies on routine fundoscopy for the clinical detection of microvascular abnormalities. However, permanent retinal damage may occur well before clinical signs are appreciable. In the early stages of DR, the retina undergoes distinct epigenetic changes, including DNA methylation and histone modifications. Recent evidence supports unique epigenetic 'signatures' in patients with DR compared to non-diabetic controls. These DNA 'signature' sequences may be specific to the retina and may circulate in peripheral blood in the form of cell-free DNA (cfDNA). In this review, we explore the literature and clinical application of cfDNA sampling as an early, non-invasive, accessible assessment tool for early DR detection. First, we summarize the known epigenetic signatures of DR. Next, we review current sequencing technologies used for cfDNA detection, such as magnetic bead-based enrichment, next-generation sequencing, and bisulfite sequencing. Finally, we outline the current research limitations and emerging areas of study which aim to improve the clinical utility of cfDNA for DR evaluation.

Diabetes mellitus (DM) is a serious health issue and is still one of the major causes of mortality around the globe. Natural products have progressively integrated into modern, advanced medical practices. Phytoconstituents from some medicinal plants have demonstrated therapeutic activity in treating different metabolic disorders and have been used to treat DM and its severe complications. The present review provides details of the major anti-diabetic targets identified in the literature and also provides comprehensive information regarding the therapeutic role of a synergy-based combination of phytoconstituents that functions by controlling specific molecular pathways synchronously by inhibiting certain key regulators involved in the development and progression of DM. The review also implicated the role of oxidative stress in diabetic complications and presented scientific validations of phytochemicals and their synergy-based combination using in vitro and or in vivo approaches.

Diabetes mellitus, particularly type 2 diabetes mellitus (T2DM), is a pervasive chronic disease that affects millions of people worldwide. It predisposes individuals to a range of severe microvascular and macrovascular complications, which drastically impact the patient's quality of life and increase mortality rates owing to various comorbidities. This extensive review explores the intricate pathophysiology underlying diabetic complications, focusing on key mechanisms, such as atherosclerosis, insulin resistance, chronic inflammation, and endothelial dysfunction. It also highlights recent therapeutic advancements, including the introduction of SGLT2 inhibitors and GLP-1 receptor agonists, which provide benefits beyond glycemic control and offer cardiovascular and renal protection. Furthermore, the future position of SGLT2 inhibitors and GLP-1 receptor agonists in terms of the prevention of diabetes and macrovascular diseases will be discussed. Considering the differences in insulin secretion capacity between Western and Asian patients, including Japanese patients, we propose a treatment strategy for high-quality diabetes in Japan.

Anxiety disorders are frequently observed in patients with diabetes and can be associated with several diabetes-related factors. Here we determine that hyperglycaemia is a major cause for the development of anxiety disorders through a C-C motif chemokine ligand 2 (CCL2)-dependent mechanism. By adopting complementary strategies, we demonstrate that neuron-specific (not peripheral) CCL2 mediates anxiety-like behaviours in streptozotocin-induced diabetic mice. Mechanistically, high glucose levels induce Tonicity-responsive enhancer-binding protein (TonEBP)-dependent CCL2 expression in neurons, leading to microglial activation in a paracrine manner. Similar phenotypes are also observed in high-fat diet-induced diabetic mice, independent of insulin signalling. Furthermore, we reveal that neuronal CCL2 in the medial prefrontal cortex and ventral hippocampus synergistically induces anxiety-like behaviours, indicating brain region-specific effects on diabetic mice. Finally, we confirm that the neuronal TonEBP-CCL2 axis and inflammatory pathways are both upregulated in patients with diabetes. Conclusively, neuronal CCL2 is specifically increased by hyperglycaemia and contributes to anxiety disorders, providing additional insights into the link between diabetes and mental health disorders.

Retinal diseases are a leading cause of vision loss, affecting millions of people worldwide. Current treatment options are based on invasive methods such as intravitreal injections. Therefore, there is a need for alternative therapeutic strategies that are both effective and more patient-friendly.

Topical drug delivery has gained attention as a preferred noninvasive approach, although it is hindered by several ocular barriers. Cyclodextrin (CD)-based nanoparticles have emerged as a promising strategy to overcome these limitations by enhancing drug permeability in the posterior segment of the eye. This review discusses the potential of CDs as enabling pharmaceutical excipients, their role in improving ocular drug bioavailability, and provides examples of CD-based eye drop formulations currently under development or undergoing clinical trials. Also, the role of CDs as active pharmaceutical agents in ophthalmology is discussed.

CD-based nanoparticle eye drops present a promising solution and have shown clinical success. CDs are approved pharmaceutical excipients for eye drop formulations and can act as active pharmaceutical ingredients for the treatment of inherent retinal diseases. Future innovations in hybrid CD-based delivery systems and integration of novel therapeutic compounds could provide more efficient and targeted treatment options for retinal diseases.

Müller cells are a crucial retinal cell type involved in multiple regulatory processes and functions that are essential for retinal health and functionality. Acting as structural and functional support for retinal neurons and photoreceptors, Müller cells produce growth factors, regulate ion and fluid homeostasis, and facilitate neuronal signaling. They play a pivotal role in retinal morphogenesis and cell differentiation, significantly contributing to macular development. Due to their radial morphology and unique cytoskeletal organization, Müller cells act as optical fibers, efficiently channeling photons directly to the photoreceptors. In response to retinal damage, Müller cells undergo specific gene expression and functional changes that serve as a first line of defense for neurons, but can also lead to unwarranted cell dysfunction, contributing to cell death and neurodegeneration. In some species, Müller cells can reactivate their developmental program, promoting retinal regeneration and plasticity-a remarkable ability that holds promising therapeutic potential if harnessed in mammals. The crucial and multifaceted roles of Müller cells-that we propose to collectively call "Müller cells trophism"-highlight the necessity of maintaining their functionality. Dysfunction of Müller cells, termed "Müller cells pathology," has been associated with a plethora of retinal diseases, including age-related macular degeneration, diabetic retinopathy, vitreomacular disorders, macular telangiectasia, and inherited retinal dystrophies. In this review, we outline how even subtle disruptions in Müller cells trophism can drive the pathological cascade of Müller cells pathology, emphasizing the need for targeted therapies to preserve retinal health and prevent disease progression.

Background and Objectives: Cardiovascular diseases are prevalent entities, especially in emergency patients. Arterial stiffness is a known predictor of cardiovascular risk and mortality and is quantified by carotid-femoral pulse wave velocity (cfPWV). It is caused in part by vascular calcification, but exact details of the underlying mechanisms are yet to be elucidated, and current data suggest endocrine influences. This study thus aimed to assess the associations of endocrine parameters, particularly thyroid and parathyroid hormones, calcium, inorganic phosphate, and vitamin D, with cfPWV as a surrogate for arterial stiffness. Materials and Methods: Adults presenting to a single tertiary care emergency department in Vienna between 2018 and 2023 were prospectively enrolled. CfPWV was measured non-invasively, and levels of thyroid and parathyroid hormones and 25-hydroxyvitamin D, calcium, and inorganic phosphate were assessed. Results: In total, data from 827 patients, predominantly male (57%) and around 60 (47-72) years of age, were assessed. We observed a significant worsening of cfPWV with increasing parathyroid hormone levels (p < 0.001) and TSH levels (p = 0.03). No significant influences of calcium, inorganic phosphate, or 25-hydroxyvitamin D were observed. Conclusions: Thyroid and parathyroid hormone levels are associated with arterial stiffness in emergency department patients, suggesting a need for a comprehensive workup in patients at risk because of comorbidities and age. Additional prospective studies are needed to further elucidate the role of endocrinology in arterial stiffness and the subsequent relevance in emergency medicine.

Diabetic neuropathy (DN) is a prevalent and debilitating complication of diabetes mellitus, significantly impacting patient quality of life and contributing to morbidity and mortality. Affecting approximately 50% of patients with diabetes, DN is predominantly characterized by distal symmetric polyneuropathy, leading to sensory loss, pain, and motor dysfunction, often resulting in diabetic foot ulcers and lower-limb amputations. The pathogenesis of DN is multifaceted, involving hyperglycemia, dyslipidemia, oxidative stress, mitochondrial dysfunction, and inflammation, which collectively damage peripheral nerves. Despite extensive research, disease-modifying treatments remain elusive, with current management primarily focusing on symptom control. This review explores the complex mechanisms underlying DN and highlights recent advances in diagnostic and therapeutic strategies. Emerging insights into the molecular and cellular pathways have unveiled potential targets for intervention, including neuroprotective agents, gene and stem cell therapies, and innovative pharmacological approaches. Additionally, novel diagnostic tools, such as corneal confocal microscopy and biomarker-based tests, have improved early detection and intervention. Lifestyle modifications and multidisciplinary care strategies can enhance patient outcomes. While significant progress has been made, further research is required to develop therapies that can effectively halt or reverse disease progression, ultimately improving the lives of individuals with DN. This review provides a comprehensive overview of current understanding and future directions in DN research and management.

Coronary atherosclerosis in patients with diabetes mellitus is the most significant pathophysiological mechanism responsible for ischemic heart disease. Atherosclerosis in diabetes is premature, more diffuse, and more progressive, and it affects more coronary blood vessels compared to non-diabetics. Atherosclerosis begins with endothelial dysfunction, continues with the formation of fatty streaks in the intima of coronary arteries, and ends with the appearance of an atherosclerotic plaque that expands centrifugally and remodels the coronary artery. If the atherosclerotic plaque is injured, a thrombus forms at the site of the damage, which can lead to vessel occlusion and potentially fatal consequences. Diabetes mellitus and atherosclerosis are connected through several pathological pathways. Among the most significant factors that lead to atherosclerosis in diabetics are hyperglycemia, insulin resistance, oxidative stress, dyslipidemia, and chronic inflammation. Chronic inflammation is currently considered one of the most important factors in the development of atherosclerosis. However, to date, no adequate anti-inflammatory therapeutic measures have been found to prevent the progression of the atherosclerotic process, and they remain a subject of ongoing research. In this review, we summarize the most significant pathophysiological mechanisms that link atherosclerosis and diabetes mellitus.

The association between thyroid-stimulating hormone (TSH) and type 2 diabetes mellitus (T2DM) is well known. However, whether TSH is related to nonproliferative diabetic retinopathy (NPDR) has not been studied. This study aimed to explore the relationship between TSH and NPDR in Chinese patients with T2DM.

In this cross-sectional study, 427 patients with T2DM were enrolled. The individuals were classified into two groups according to the fundus oculi examination: the non-diabetic retinopathy (NDR) group (n = 224) and the non-proliferative diabetic retinopathy (NPDR) group (n = 203). The individuals' demographic and clinical data were collected by reviewing medical records and direct interviews. The demographic data and biochemical parameters were compared between groups using the Student's t - test or the Mann‒Whitney U test, anthropometric measurements, thyroid function, and NPDR were evaluated, and the associations between TSH and NPDR were assessed using logistic regression models.

No significant differences in age, sex, body mass index (BMI), incidence of alcohol consumption, and duration of diabetes were found between these two groups. The systolic blood pressure (SBP), incidence of smoking, TSH, blood urea nitrogen (BUN), and urinary micro-albumin (mALB) were significantly higher in the NPDR group than in the NDR group (P < 0.05). Individuals in the NDR group had higher levels of thyroxine (T4), glutamic pyruvic transaminase (ALT), fasting C-peptide (FCP), and 2-hour C-peptide (2hCP) than individuals in the NPDR group (P < 0.05). Spearman's correlation analysis revealed that the serum TSH levels were negatively associated with the HbA1c levels in all patients (r=-0.11, P < 0.05). Serum TSH levels were negatively correlated with HbA1c levels (r = -0.19, P < 0.01) and positively correlated with diabetes duration (r = 0.14, P < 0.05) in the NPDR group. Multivariate logistic regression analysis revealed that high TSH levels, sex, diabetes duration, high-density lipoprotein cholesterol (HDL-C), glycosylated hemoglobin (HbA1c), FCP, and SBP were associated with NPDR [odds ratio (OR) > 1, P < 0.05]. Receiver operating characteristic curve analysis revealed that the optimal cutoff point of TSH for predicting NPDR was 2.235 mIU/L.

The TSH level is independently associated with NPDR in the Chinese population with T2DM. A high serum TSH level may be a potential risk factor for NPDR and an indicator for screening for diabetic microangiopathy.

This study is registered with the Chinese Clinical Trial Registry (02/21/2025 ChiCTR2500097614).

Cardiovascular disease (CVD) remains a major global health challenge, particularly affected by glucose metabolism status. However, the relationship between estimated glucose disposal rate (eGDR) and future CVD risk across different glucose metabolism status remains unclear.

We analyzed data from the China Health and Retirement Longitudinal Study (2011-2020) of participants aged ≥ 45 years. The eGDR was calculated using waist circumference, hypertension status, and HbA1c levels. CVD events (stroke or cardiac events) were the outcome. Participants were categorized by glucose metabolism status (normoglycemia, prediabetes, diabetes). Cox proportional hazards models and restricted cubic splines were used to assess associations and potential non-linear relationships.

Among 7,828 participants (52.84% male, mean age 59.01 ± 9.21 years) followed for an average of 8.29 years, 1,944 participants (24.83%) developed CVD. Higher eGDR was inversely associated with CVD risk across all glucose metabolism states. Below the inflection points (11.77, 11.15, and 11.56 mg/kg/min for normoglycemia, prediabetes, and diabetes, respectively), each 1-unit increase in eGDR reduced CVD risk by 14% (HR = 0.86, 95%CI: 0.83-0.89), 10% (HR = 0.90, 95%CI: 0.86-0.93), and 14% (HR = 0.86, 95%CI: 0.81-0.91), respectively.

The eGDR demonstrates a potentially non-linear inverse association with future CVD risk across different glucose metabolism states.

Primary hypertension is the most common type of hypertension, with a complex and not fully understood pathogenesis. Insulin resistance (IR) is a metabolic abnormality that has been shown to be quite prevalent among patients with hypertension in existing literature. The triglyceride-glucose (TyG) index is a reliable indicator for assessing insulin resistance (IR). This study aims to evaluate the relationship between the TyG index at admission and all-cause mortality (ACM) in patients with severe primary hypertension, and to explore its role in predicting the future all-cause mortality risk in primary hypertension patients. This study employs a retrospective design to categorize all patients into four quartiles based on the TyG index. The Kaplan-Meier (K-M) method was utilized to estimate the survival curves for each group and to compare the survival outcomes across different quartiles. To assess the nonlinear relationship between the TyG index and prognosis, Cox proportional hazards regression models and restricted cubic splines (RCS) were applied, adjusting for potential confounders. Additionally, subgroup analyses were performed to conduct stratified analyses and interaction tests. Kaplan-Meier survival curve analysis showed that patients with higher TyG index levels had higher all-cause mortality rates at 30 days, 60 days, and 90 days post-admission. This indicates that a higher TyG index is associated with an increased risk of death in the short term. Additionally, multivariate Cox proportional hazards regression analysis revealed that an increased TyG index was significantly associated with all-cause mortality at 30 days, 60 days, and 90 days. Meanwhile, RCS analysis indicates that as the TyG index level increases, the hazard ratio (HR) shows a significant upward trend, suggesting a gradual increase in the risk of all-cause mortality. In summary, among patients with primary hypertension in the intensive care unit, elevated TyG levels are associated with an increased risk of short-term mortality.

Although advanced surgical techniques are available, satisfactory functional outcomes after peripheral nerve injuries are uncommon. Hence, immune-modulating factors such as PXL01, a lactoferrin-derived peptide that improves axonal outgrowth in injured human digital nerves, have gained attention. We previously reported a short-term immunosuppressive effect of PXL01 after the repair of transected rat sciatic nerves, but it had no effect on nerve regeneration. Here, we investigated the potential of PXL01 to improve nerve regeneration in healthy rats and in a rat model of type 2 diabetes (Goto-Kakizaki [GK] rats).

A 10-mm sciatic nerve defect was created in healthy (n = 14) and diabetic GK rats (n = 14) and reconstructed using nerve autografts. Immediately after surgery, PXL01 or sodium chloride (control, placebo) (n = 7 for each treatment) was administered around the autograft. On day 8, immunohistochemical staining of the sciatic nerve and dorsal root ganglia (DRGs) was performed to analyze axonal outgrowth (neurofilament staining); inflammation (CD68 and CD206 macrophage staining in nerve); Schwann cell and sensory neuron activation (transcription factor ATF3 staining in nerve and DRGs) and apoptosis (cleaved caspase 3 staining in nerve); and neuroprotection (heat shock protein [HSP27] staining in nerve and DRGs).

PXL01 had no impact on the macrophage response in the autografts but increased axonal outgrowth and HSP27 expression in the DRGs of healthy and diabetic rats, despite a lower number of activated Schwann cells in the autograft. Diabetes affected axonal outgrowth, Schwann cell and macrophage responses, and HSP27 expression. These effects were observed in the sciatic nerve as well as the DRG.

Application of PXL01, despite having no impact on macrophages, may improve axonal outgrowth and affects Schwann cell activation in autograft-reconstructed sciatic nerves, as well as conveys neuroprotection (HSP27 expression) in the DRGs of healthy and diabetic GK rats. Diabetes influenced nerve regeneration in such autografts. Therefore, PXL01 is a promising candidate to improve nerve regeneration.

Diabetic kidney disease (DKD) is the leading cause of end-stage renal disease (ESRD), affecting over 40% of patients with diabetes. DKD progression involves fibrosis and damage to glomerular and tubulointerstitial regions, with mitochondrial dysfunction playing a critical role. Impaired mitochondria lead to reduced adenosine triphosphate (ATP) production, damaged mitochondria accumulation, and increased reactive oxygen species (ROS), contributing to renal deterioration. Maintaining mitochondrial quality control (MQC) is essential for preventing cell death, tissue injury, and kidney failure. Recent clinical trials show that enhancing MQC can alleviate DKD. However, current treatments cannot halt kidney function decline, underscoring the need for new therapeutic strategies. Mitochondrial-targeted drugs show potential; however, challenges remain because of adverse effects and unclear mechanisms. Future research should aim to comprehensively explore therapeutic potential of MQC in DKD. This review highlights the significance of MQC in DKD treatment, emphasizing the need to maintain mitochondrial quality for developing new therapies.

This study aimed to assess the relationship between hemoglobin glycation index (HGI) and risk of rapid kidney function decline (RKFD) in diabetic patients.

HGI was calculated as actual measured HbA1c minus predicted HbA1c. RKFD was defined as a 30 % decline in estimated glomerular filtration rate during follow-up. Participants were categorized into three groups based on HGI levels: lower (HGI ≤ -0.55), medium (-0.55 < HGI ≤ 0.22) and higher (HGI > 0.23). To understand the association between HGI and risk of RKFD in diabetic patients, directed acyclic graph were drawn and multivariate Cox proportional hazards models were used to adjust for covariates.

During a median follow-up of 4.0 years, RKFD occurred in 43 patients (6.3 %) with diabetes. After adjusting for potential confounders, Compared to the lower-HGI group, the hazard ratios for RKFD were 1.75 (95 % confidence interval [95 % CI]: 0.72, 4.25) and 2.64 (95 % CI: 1.12, 6.21) in the medium- and higher-HGI groups, respectively. HGI showed a linearly associated with RKFD (Pfor nonlinear = 0.383). The magnitude of associations was not materially altered in all sensitivity analyses, but with none significantly.

Higher HGI may be associated with an increased risk of RKFD in diabetic patients.

Early detection and intervention are vital for managing type 2 diabetes mellitus (T2DM) effectively. However, it's still unclear which risk factors for T2DM onset are most significant. This study aimed to use cluster analysis to categorize individuals based on six known risk factors, helping to identify high-risk groups requiring early intervention to prevent T2DM onset.

This study comprised 7402 Korean Genome and Epidemiology Study individuals aged 40 to 69 years. The hybrid hierarchical k-means clustering algorithm was employed on six variables normalized by Z-score-age, triglycerides, total cholesterol, non-high-density lipoprotein cholesterol, high-density lipoprotein cholesterol and C-reactive protein. Multivariable Cox proportional hazard regression analyses were conducted to assess T2DM incidence.

Four distinct clusters with significantly different characteristics and varying risks of new-onset T2DM were identified. Cluster 4 (insulin resistance) had the highest T2DM incidence, followed by Cluster 3 (inflammation and aging). Clusters 3 and 4 exhibited significantly higher T2DM incidence rates compared to Clusters 1 (healthy metabolism) and 2 (young age), even after adjusting for covariates. However, no significant difference was found between Clusters 3 and 4 after covariate adjustment.

Clusters 3 and 4 showed notably higher T2DM incidence rates, emphasizing the distinct risks associated with insulin resistance and inflammation-aging clusters.

Accelerated Pancreatic β-cell apoptosis and oxidative stress are the mainstays of type-1 diabetes. MicroRNA-21's (miRNA-21) role in regulating pancreatic β-cell function remains indefinable.

Five groups of rats were used in this study (healthy controls (Ia), controls that received only chitosan (CS) nanoparticles (NPs)(Ib), streptozotocin (STZ)-induced diabetics rats (II),STZ-induced diabetic rats that received only CS-NPs(III), and STZ-induced diabetic rats treated with mi-RNA-21-CS-NPs(IV). Sera were collected for measurement of fasting blood glucose levels (FBG), insulin, oxidative stress, and intraperitoneal glucose intolerance tests. Pancreatic tissue was collected after sacrifice partly for histological examination and for oxidative stress assessment and evaluation of PTEN/ AKT using qRT-PCR.

We showed over-expression of cleaved-caspase-3 indicating accelerated apoptosis in the β-cell of STZ-induced diabetic rats. Apoptosis was significantly ameliorated by miRNA-21-CS. MiRNA-21-CS-NPs faithfully restored serum fasting insulin, and FBG, and reduced serum and pancreatic oxidative stress markers while enhancing the total antioxidant capacity. Histological examination revealed that miRNA-21 restored healthy β-cell architecture, decreased cleaved-caspase-3, and increased insulin secretion. Transmission electron microscopy revealed increased mitochondrial circularity that significantly correlated with an exaggerated oxidative stress profile as shown by high serum and pancreatic malondialdehyde (MDA), low glutathione peroxidase, and total antioxidant capacity in STZ-induced diabetes. This oxidative profile was reversed using miRNA-21-CS-NPs. Mi-RNA-21 therapy downregulated PTEN but increased AKT and pAKT expression. Altogether, we show that miRNA-21 restored normal islet β-cell structure and insulin secretion through PTEN inhibition.

miRNA-21- CS-NPs are promising targeted therapeutics that may effectively decrease the global burden of diabetes.

To compare the impact of sodium-glucose cotransporter 2 (SGLT2) and dipeptidyl peptidase 4 (DPP-4) inhibitors on age-related macular degeneration (AMD) risk among patients with type 2 diabetes mellitus (T2DM).

This multinational, retrospective cohort study used electronic medical records from healthcare institutions across 21 countries. Adults 50 years or older with T2DM who had a prior prescription of metformin and initiated SGLT2 or DPP-4 inhibitors from 2013 to 2023 were included. The SGLT2 and DPP-4 inhibitor groups were propensity score matched in a 1:1 ratio to balance baseline characteristics and were followed for up to 5 years to observe the occurrence of AMD. Statistical analysis was performed using the Cox proportional hazards model and Kaplan-Meier analysis.

Our final analysis included 20,966 T2DM patients prescribed SGLT2 inhibitors and 20,966 prescribed DPP-4 inhibitors. Compared to the DPP-4 inhibitor group, the SGLT2 inhibitor group was associated with significantly lower risks of AMD (hazard ratio [HR], 0.71; 95% confidence interval [CI], 0.58-0.85) and dry AMD (HR, 0.61; 95% CI, 0.46-0.80) but not wet AMD (HR, 0.74; 95% CI, 0.48-1.16). SGLT2 inhibitors compared with DPP-4 inhibitors were linked to a reduced risk of AMD in the White population, patients prescribed empagliflozin or dapagliflozin, and individuals with glycated hemoglobin < 8.5%, estimated glomerular filtration rate ≥ 60 mL/min/1.73 m2, hypertension, or dyslipidemia, regardless of body mass index level.

In patients with T2DM, those prescribed SGLT2 inhibitors may experience lower risks of AMD and dry AMD compared to those prescribed DPP-4 inhibitors.

Diabetic retinopathy, a microvascular complication of diabetes, is the leading cause of blindness in adults, but the molecular mechanism of its development remains unclear. Retinal mitochondrial DNA is damaged and hypermethylated, and mtDNA-encoded genes are downregulated. Expression of a long noncoding RNA (larger than 200 nucleotides, which does not translate into proteins), encoded by mtDNA, cytochrome B (LncCytB), is also downregulated. This study aims to investigate the role of DNA methylation in the downregulation of LncCytB in diabetic retinopathy. Human retinal endothelial cells, incubated in 5 mM (normal) or 20 mM (high) D-glucose, in the presence/absence of Azacytidine (a DNA methyl transferase inhibitor) were analyzed for LncCytB DNA methylation by immunoprecipitation and methylation specific PCR techniques, and LncCytB transcripts by strand-specific PCR and RNA-FISH. Mitochondrial genomic stability was evaluated by quantifying protective mtDNA nucleoids by SYBR green staining and by flow cytometry, and functional stability by oxygen consumption rate using Seahorse analyzer. Results were confirmed in an in vivo model using retina from diabetic rat. While high glucose elevated 5 mC and the ratio of methylated to unmethylated amplicons at LncCytB and downregulated its transcripts, azacytidine prevented LncCytB DNA hypermethylation and decrease in its expression. Azacytidine also ameliorated decrease in nucleoids and oxygen consumption rate. Similarly, azacytidine prevented increase in retinal LncCytB DNA methylation and decrease in its expression in diabetic rats. Thus, DNA hypermethylation plays a major role in the downregulation of retinal LncCytB in diabetes, resulting in impaired mitochondrial homeostasis, and culminating in the development of diabetic retinopathy.

Hypoxia stimulates glucose uptake independently from the action of insulin. The purpose of this study was to determine the effect of intermittent hypoxia, consisting of alternating short bouts of breathing hypoxic and room air, on glucose concentration, insulin concentration, and insulin sensitivity during an oral glucose tolerance test in adults with type 2 diabetes and adults with normal glycemic control. Nine adults with type 2 diabetes (2 women, HbA1c: 7.3 ± 1.5%, age: 52 ± 13 yr) and nine adults with normal glycemic control (4 women, HbA1c: 5.4 ± 0.1%, age: 24 ± 4 yr) performed a 2-h oral glucose tolerance test on two separate visits to the laboratory. Following ingestion of the glucose drink, participants were exposed to either an intermittent hypoxia protocol, consisting of eight 4-min hypoxic cycles at a targeted oxygen saturation of 80% interspersed with breathing room air to resaturation, or a sham protocol consisting of eight 4-min normoxic cycles interspersed with breathing room air. Intermittent hypoxia did not attenuate the increase in glucose concentration but attenuated the increase in insulin concentration in response to an oral glucose tolerance test in comparison with the sham protocol in adults with type 2 diabetes. Insulin sensitivity was greater during intermittent hypoxia in comparison with the sham protocol in adults with type 2 diabetes (0.043 ± 0.036 vs. 0.032 ± 0.046 μmol/kg/min/pmol, P = 0.01), but did not change in the control group (0.122 ± 0.015 vs. 0.128 ± 0.008 μmol/kg/min/pmol, P = 0.12). In conclusion, intermittent hypoxia improved insulin sensitivity in adults with type 2 diabetes.NEW & NOTEWORTHY The aim of this study was to determine the effect of short bouts of hypoxia, which stimulates glucose uptake, on glucose concentration, insulin concentration, and insulin sensitivity during an oral glucose tolerance test in adults with type 2 diabetes and adults with normal glycemic control. Intermittent hypoxia acutely improved insulin sensitivity in adults with type 2 diabetes.

The hyperglycemic microenvironment of diabetes inevitably leads to the accumulated reactive oxygen species (ROS) and impairs the function of stem cells, thereby impeding the process of osseointegration after implant placement. In this study, a self-assembled metal-phenolic nanozyme coating is presented for alleviating diabetic oxidative stress and improving osseointegration at implant interfaces. The antioxidant-like enzyme activity is induced by phenolic ligand-metal charge transfer (LMCT) during the coordination of epigallocatechin-3-gallate (EGCG) with copper phosphate nanosheets (Cu NS). The metal-phenolic nanozyme biointerfaces exhibits scavenging activity against a range of free radicals and facilitated the adhesion, migration, and osteogenic differentiation of stem cells, thereby enhancing the osseointegration of implants in diabetic rats. Additionally, the nanozyme coating strategy inhibits bacterial invasion and supports the adhesion of soft tissue cells. This study provides a prospective approach for surface modification to safeguard and enhance the osseointegration of implants in diabetic subjects.