Evolving Global Etiology of Hepatocellular Carcinoma (HCC): Insights and Trends for 2024.

The epidemiology of HCC is changing all over the world and the incidence of HCC is expected to continue increasing over the next 30 years. The changes are in the predisposing factors. Hepatitis B and hepatitis C as predisposing etiologies are decreasing while NAFLD/MAFLD is increasing. The increase in MAFLD is so great that despite the decrease in hepatitis B and C, the overall incidence of HCC is increasing. HCC in persons below the age of 20 years has distinct characteristics different from that of HCC in adults. The changing etiology of hepatocellular carcinoma has implications for the early detection, prevention, the stage of HCC at time of detection and in the treatment of HCC. The extent of these changes and their significance are discussed.

Addressing disparities in the long-term mortality risk in individuals with non-ST segment myocardial infarction (NSTEMI) by diabetes mellitus status: a nationwide cohort study.

AIMS/HYPOTHESIS: The aim of this study was to investigate how diabetes mellitus affects longer term outcomes in individuals presenting to hospital with non-ST segment elevation myocardial infarction (NSTEMI). METHODS: We analysed data from 456,376 adults hospitalised between January 2005 and March 2019 with NSTEMI from the UK Myocardial Ischaemia National Audit Project (MINAP) registry, linked with Office for National Statistics death reporting. We compared outcomes and quality of care by diabetes status. RESULTS: Individuals with diabetes were older (median age 74 vs 73 years), were more often of Asian ethnicity (13% vs 4%) and underwent revascularisation (percutaneous coronary intervention or coronary artery bypass graft surgery) (38% vs 40%) less frequently than those without diabetes. The mortality risk for those with diabetes compared with those without was significantly higher at 30 days (HR 1.19, 95% CI 1.15, 1.23), 1 year (HR 1.28, 95% CI 1.26, 1.31), 5 years (HR 1.36, 95% CI 1.34, 1.38) and 10 years (HR 1.39, 95% CI 1.36, 1.42). In individuals with diabetes, higher quality inpatient care, assessed by opportunity-based quality indicator (OBQI) score category ('poor', 'fair', 'good' or 'excellent'), was associated with lower mortality rates compared with poor care (good: HR 0.74, 95% CI 0.73, 0.76; excellent: HR 0.69, 95% CI 0.68, 0.71). In addition, compared with poor care, excellent care in the diabetes group was associated with the lowest mortality rates in the diet-treated and insulin-treated subgroups (diet-treated: HR 0.64, 95% CI 0.61, 0.68; insulin-treated: HR 0.69, CI 0.66, 0.72). CONCLUSION/INTERPRETATION: Individuals with diabetes experience disparities during inpatient care following NSTEMI. They have a higher risk of long-term mortality than those without diabetes, and higher quality inpatient care may lead to better long-term survival.

Validation of plasma neutrophil gelatinase-associated lipocalin as a biomarker for diabetes-related acute kidney injury.

OBJECTIVE: This retrospective study aimed to investigate the correlation between neutrophil gelatinase-associated lipocalin (NGAL) levels and the clinical progression and severity of diabetes-related acute kidney injury (AKI). The quantitative determination of NGAL in plasma on the Beckman Coulter AU480 analyzer was measured using the Bioporto NGAL TestTM, a particle-enhanced turbidimetric immunoassay with hospitalized patients at an East Central Georgia Medical Center. METHODS: The clinical determination of plasma NGAL included a retrospective cohort study where 45 adult patients were selectively recruited. The selective criteria were patients with and without diabetes mellitus (DM) at risk for developing AKI admitted to the Medical Center between January and November 2023. All patients included in the study had pNGAL levels measured upon admission and up to 96 h post-admission. Receiver operating characteristics and likelihood ratio methods were used to determine optimal sensitivity, specificity, and cutoff value of pNGAL in AKI patients associated with and without DM. RESULTS: The intra-assay and interassay imprecision percent relative standard deviation was between 2.7% and 4.2%. pNGAL levels were higher for patients with AKI compared to non-AKI patients, regardless of DM status. The optimal cutoff value for pNGAL to predict AKI for patients with DM was 293 ng/mL, with a sensitivity of 80% and specificity of 87%. In a multivariate logistic regression model, pNGAL levels at 48 h post-admission were determined to be associated with diabetes-related AKI patients. CONCLUSION: Plasma NGAL levels at 48 h are associated with patients with diabetes-related AKI. The specific cutoff values for AKI for early diagnosis and risk stratification and its association with comorbidities must be determined to improve patient outcomes.

Optimal tactics for surgical revascularisation in diabetic angiopathy of the lower limbs.

OBJECTIVE: Aim: This study aims to compare the efficacy of conservative treatment methods versus advanced surgical interventions, including revascularising automyelotransplantation and stem cell therapy, in improving vascular patency and the quality of life in patients with diabetic angiopathy. PATIENTS AND METHODS: Materials and Methods: The research analyzed 68 patients with angiopathies under medical supervision from January 2007 to December 2017 at the National Scientific Center of Surgery named after A.N. Syzganov. Participants, aged 4 to 49, were divided into two groups based on angiographic blood flow characteristics: one with accelerated and another with delayed blood flow. A comprehensive participant selection process was implemented to ensure a representative sample. Sensitivity analysis was conducted to validate the findings' robustness. RESULTS: Results: The main group demonstrated notable success in limb salvage, with 90.9% avoiding high limb amputation post-revascularising automyelotransplantation. Moreover, 16.7% of patients experienced healing of trophic ulcers and toe necrosis. The use of stem cells from adipose tissue and fetal tissue progenitor cells showed promising results in reducing pain and increasing pain-free walking distance, alongside the formation of collateral vascular networks. CONCLUSION: Conclusions: The study concludes that advanced surgical interventions and stem cell therapies significantly enhance treatment outcomes in patients with diabetic angiopathy compared to conventional conservative treatments. These findings highlight the potential of personalized and innovative approaches in managing vascular complications associated with diabetes, offering new avenues for reducing disability and improving patient quality of life. Future research should focus on further refining these therapeutic strategies and exploring their integration into clinical practice.

Bone marrow mesenchymal stem cell and mononuclear cell combination therapy in patients with type 2 diabetes mellitus: a randomized controlled study with 8-year follow-up.

BACKGROUND: To investigate the long-term effects of combining bone marrow mesenchymal stem cells (MSCs) with mononuclear cells (MCs) in the treatment of type 2 diabetes mellitus (T2DM). METHODS: T2DM patients were divided into the combination group (Dual MSC + MC, n = 33), the mononuclear cell group (MC-Only, n = 32) and the control group (Control, n = 31). All groups were treated with insulin and metformin. The Dual MSC + MC group additionally received MSC and MC infusion and the MC-Only group additionally received MC infusion. The patients were followed up for 8 years. The primary endpoint was the C-peptide area under the curve (C-p AUC) at 1 year. This study was registered with clinicaltrial.gov (NCT01719640). RESULTS: A total of 97 patients were included and 89 completed the follow-up. The area under the curve of C-peptide of the Dual MSC + MC group and the MC-Only group was significantly increased (50.6% and 32.8%, respectively) at 1 year. After eight years of follow-up, the incidence of macrovascular complications was 13.8% (p = 0.009) in the Dual MSC + MC group and 21.4% (p = 0.061) in the MC-Only group, while it was 44.8% in the Control group. The incidence of diabetic peripheral neuropathy (DPN) was 10.3% (p = 0.0015) in the Dual MSC + MC group, 17.9% (p = 0.015) in the MC-Only group, and 48.3% in the Control group. CONCLUSIONS: The combination of MSC and MC therapy can reduce the incidence of chronic diabetes complications and improves metabolic control with mild side effects in T2DM patients.

Glucagon-like peptide 1 receptor agonist: A potential game changer for cholangiocarcinoma.

Glucagon-like peptide-1 receptor (GLP-1R) agonist, a subgroup of incretin-based anti-diabetic therapies, is an emerging medication with benefits in reducing blood glucose and weight and increasing cardiovascular protection. Contrarily, concerns have been raised about GLP-1R agonists increasing the risk of particular cancers. Recently, several epidemiological studies reported contradictory findings of incretin-based therapy on the risk modification for cholangiocarcinoma (CCA). The first cohort study demonstrated that incretin-based therapy was associated with an increased risk of CCA. Later studies, however, showed a null effect of incretin-based therapy on CCA risk for dipeptidyl peptidase-4 inhibitor nor GLP-1R agonist. Mechanistically, glucagon-like peptide 1 receptor is multifunctional, including promoting cell growth. High GLP-1R expressions were associated with progressive phenotypes of CCA cells in vitro. Unexpectedly, the GLP-1R agonist showed anti-tumor effects on CCA cells in vitro and in vivo with unclear mechanisms. Our recent report also showed that GLP-1R agonists suppressed the expression of GLP-1R in CCA cells in vitro and in vivo, leading to the inhibition of CCA tumor growth. This editorial reviews recent evidence, discusses the potential effects of GLP-1R agonists in CCA patients, and proposes underlying mechanisms that would benefit from further basic and clinical investigation.

Reference gene panel for urinary exosome-based molecular diagnostics in patients with kidney disease.

BACKGROUND: Kidney disease is a severe complication of diabetes that often leads to end-stage renal disease. Early diagnosis is crucial for prevention or delay. However, the current diagnostic methods, with their limitations in detecting the disease in its early stages, underscore the urgency and importance of finding new solutions. miRNAs encapsulated inside urinary exosomes (UEs) have potential as early biomarkers for kidney diseases. The need for reference miRNAs for accurate interpretation currently limits their translational potential. AIM: To identify consistently expressing reference miRNAs from UEs of controls and patients with type 2 diabetesmellitus (T2DM) and biopsy-confirmed kidney diseases. METHODS: miRNA profiling was performed on UEs from 31 human urine samples using a rigorous and unbiased method. The UEs were isolated from urine samples collected from healthy individuals (n = 6), patients with T2DM (n = 13), and T2DM patients who also had kidney diseases (including diabetic nephropathy, n = 5; membranous nephropathy, n = 5; and IgA nephropathy, n = 2) through differential ultracentrifugation. After characterizing the UEs, miRNA expression profiling using microarray technology was conducted. RESULTS: Microarray data analysis identified 14 miRNAs that were consistently expressed in UEs from 31 human samples, representing various kidney conditions: diabetic controls, diabetic nephropathy, membrane nephropathy, IgA nephropathy, and healthy controls. Through in silico analysis, we determined that 10 of these miRNAs had significant potential to serve as reference genes in UEs. CONCLUSION: We identified uniformly expressing UE miRNAs that could serve as reference genes kidney disease biomarkers.

Quercetin prevents rats from type 1 diabetic liver damage by inhibiting TGF-ꞵ/apelin gene expression.

Background: Hyperglycemia-induced oxidative stress is a significant contributor to diabetic complications, including hepatopathy. The current survey aimed to evaluate the ameliorative effect of quercetin (Q) on liver functional disorders and tissue damage developed by diabetes mellitus in rats. Methods: Grouping of 35 male Wistar rats was performed as follows: sham; sham + quercetin (sham + Q: quercetin, 50 mg/kg/day in 1 ml 1% DMSO for 6 weeks, by gavage); diabetic control (Diabetes: streptozotocin (STZ), 65 mg/kg, i.p.); diabetic + quercetin 1 (D + Q1: quercetin, 25 mg/kg/day in 1 ml 1% DMSO for 6 weeks, by gavage after STZ injection); and diabetic + quercetin 2 (D + Q2: quercetin, 50 mg/kg/day in 1 ml 1% DMSO for 6 weeks, by gavage after STZ injection). Body weight, food intake, and water intake were measured. Ultimately, the samples of plasma and urine, as well as tissue samples of the liver and pancreas were gathered for later assays. Results: STZ injection ended in elevated plasma blood glucose levels, decreased plasma insulin levels, liver dysfunction (increased activity levels of AST, ALT, and ALP, increased plasma levels of total bilirubin, cholesterol, LDL, triglyceride, decreased plasma levels of total protein, albumin and HDL), enhanced levels of malondialdehyde, diminished activities of antioxidant enzymes (superoxide dismutase, and catalase), reduced level of glutathione (GSH) increased gene expression levels of apelin and TGF-ꞵ, plus liver histological destruction. All these changes were diminished by quercetin. However, the measure of improvement in the D + Q2 group was higher than that of the D + Q1 group. Conclusions: Quercetin improved liver function after diabetes mellitus type 1, possibly due to reduced lipid peroxidation, increased antioxidant systems, and inhibiting the apelin/TGF-ꞵ signaling pathway.

Associations between polychlorinated biphenyls and cancer risk among type 2 diabetes: The modifying effects of lifestyle.

A growing percentage of diabetes-related deaths has been attributed to cancer, with environmental factors playing important contributions. Thus, we studied the potential relationship between endocrine disruptors polychlorinated biphenyls (PCBs) and cancer risk in diabetes. We aimed to evaluate the association between serum seven indicator-PCB (PCB-28/52/101/118/138/153/180) levels and incident cancer, and further explore the possible modifying role of lifestyle. A total of 2806 type 2 diabetes mellitus (T2DM) cases were included from the Dongfeng-Tongji cohort at the baseline in 2008 and tracked until December 2018, and 320 incident cancers were identified during about 10-year follow-up. Cox proportional hazards models and competing risk regression models were used to reveal associations of baseline concentrations of PCBs with total cancer and specific cancer, respectively. Lifestyle score was determined by body mass index, waist circumference, physical activity, smoking, alcohol drinking, and diet. Each interquartile range (IQR) increment of non-dioxin-like PCBs (NDL-PCBs) generated an 8%-30% increase in cancer incidence. Individuals in the highest quartile for PCB-52, PCB-101, PCB-138, and lowly chlorinated PCBs had 1.44- to 1.68-fold higher cancer risk compared to those in the lowest quartile. Restricted cubic spline analyses and the quantile g-computation model showed similar results. Significant interactions were found between PCBs and fasting blood glucose or simplified insulin resistance assessment indicators. NDL-PCBs were positively and significantly associated with gastrointestinal cancer and respiratory cancer, especially with liver cancer, colorectal cancer, and lung cancer. Higher PCBs showed a significant increase in total cancer risk among participants with an unhealthy lifestyle, however, no associations were observed in those with a relatively healthy lifestyle (Pinteraction < 0.05). Our findings indicated an increased cancer risk associated with NDL-PCBs, highlighted the role of a healthy lifestyle in potentially reducing adverse impact, and provided preliminary data for environmental and public health interventions to alleviate the risk of cancer among diabetes.

Association Between Type 1 Diabetes Mellitus and Incident Gastrointestinal Cancer in Korean Population: A Nationwide Retrospective Cohort Study.

BACKGROUND: The age-standardised incidence ratio of gastrointestinal cancers in type 1 diabetes (T1D) patients has been reported to be higher than that in the general population. After adjusting for shared risk factors, we aimed to explore the association between T1D and gastrointestinal cancer and examine how this relationship varies by age and sex. MATERIALS AND METHODS: This retrospective cohort study included 268,179 participants from the Korean National Health Insurance Service-National Sample Cohort. The primary outcome is the incident of gastrointestinal cancers, based on diagnostic codes. Multivariate Cox regression analyses were performed to assess the association between T1D and gastrointestinal cancers. RESULTS: Of the 268,179 participants, 2681 had T1D at baseline and were followed for 12.98 (± 2.92) years. Compared with non-T1D, T1D patients had a significantly increased risk of all gastrointestinal cancer (adjusted hazard ratio [aHR]: 1.403, 95% confidence interval [CI]: 1.253-1.573). T1D patients increased risks of oesophageal cancer (aHR: 1.864, 95% CI: 1.038-3.349), gastric cancer (aHR: 1.313, 95% CI: 1.066-1.616), colon cancer (aHR: 1.365, 95% CI: 1.110-1.678), liver cancer (aHR: 1.388, 95% CI: 1.115-1.727), and pancreatic cancer (aHR: 1.716, 95% CI: 1.182-2.492). The consistency of this association persisted among both male and female, with its strength increasing with older age. CONCLUSIONS: The risk of gastrointestinal cancer was significantly increased in T1D patients. Older male T1D patients exhibit a higher risk, suggesting the need for targeted attention in their care.

Tangerine Peel-Derived Exosome-Like Nanovesicles Alleviate Hepatic Steatosis Induced by Type 2 Diabetes: Evidenced by Regulating Lipid Metabolism and Intestinal Microflora.

Purpose: Non-alcoholic fatty liver disease (NAFLD) represents a significant global health burden, exhibiting a strong correlation with insulin resistance, obesity, and type 2 diabetes (T2DM). Despite the severity of hepatic steatosis in T2DM patients, no specific drugs have been approved for clinical treatment of the disease. Tangerine peel is one kind of popular functional food and reported to possess hypoglycemic and lipid-lowering potential. In this study, we investigated the effects of Tangerine-peel-derived exosome-like nanovesicles (TNVs) on hepatic lipotoxicity associated with T2DM. Methods: The TNVs was prepared by differential centrifugation of the aqueous extract of Tangerine and chemical properties were characterized using transmission electron microscopy (TEM), nanoparticle tracking analysis (NTA) and LC-MS/MS. The hypoglycemic and lipid-lowering potential of TNVs were possessed by biochemical measurement, RT-PCR, 16S rRNA sequencing, GC/MS, UHPLC-MS/MS, in vivo small animal imaging assay and HE staining. Subsequently, effects of TNVs on lipid accumulation and glycolysis were investigated on 3T3-L1 and AML-12 cells. Results: TNVs significantly inhibited insulin resistance, reduced hepatic lipid accumulation, facilitate intestinal mucosal repair, rescued gut microbiota dysbiosis, regulated colonic SCFA and liver bile acid metabolism in db/db mice. Furthermore, TNVs restored the expression of key genes in glucose and lipid metabolism (ACC, AMPK, CD36, LXRα, PPAR-γ, SREBP-1) while activating the expression of genes related to glycolysis (G6Pase, GLUT2, PCK1, PEPCK) in db/db mice. Further cell-based mechanistic studies revealed that TNVs reduced lipid accumulation in 3T3-L1 and AML-12 cells via regulation of glucose and lipid metabolism-related genes (UCP1, FGFR4, PRDM16, PGC-1α, Tmem26, Cpt1, Cpt2 and PPAR-α). Conclusion: We for the first time demonstrated that TNVs could significantly improve glucose and lipid metabolism via activating the expression of genes related to fatty acid ß-oxidation and glycolysis.

The Association Between Vitamin B12 Deficiency and Diabetic Foot Ulcer in Type 2 Diabetic Patients in Qassim Province, Saudi Arabia: A Case-Control Study.

Background Diabetic foot ulcer (DFU) is a major complication of diabetes with many identified risk factors. These include poor control of diabetes, cardiovascular disease, smoking, and end-stage kidney disease. This study aims to shed light on the micronutrient status of diabetic patients and its effect on DFU, particularly, the association between vitamin B12 deficiency and DFU. Methodology This retrospective case-control study included adults in Buraydah who were at least 18 years old and had type 2 diabetes mellitus. Data were obtained from the electronic files of the patients who visited the diabetes center from January 2018 to August 2023 and were analyzed using SPSS version 27.0.1 (IBM Corp., Armonk, NY, USA). Results The research involved 221 participants, with 114 controls (individuals with diabetes but no DFU), and 107 cases (individuals with diabetes affected by DFU). Vitamin B12 levels varied, with 79.2% falling within the normal range of 187-883 pg/mL. The average age of cases (58.5 years, SD = 11.3) was notably higher than that of controls (54.1 years, SD = 14.1). Glycated hemoglobin levels were significantly higher in cases (8.7, SD = 2.0) compared to controls (7.6, SD = 2.2) (p < 0.001). Regarding physical activity, cases showed a significantly higher percentage of inactivity (62.1%) compared to controls (39.1%) (p = 0.046). Neuropathy exhibited a significant association with ulcer development, with 59.1% of cases having neuropathy compared to 23.5% of controls (p < 0.001). Furthermore, complications such as dry foot and fissures (60.0% vs. 6.3%), Charcot joint (36.8% vs. 12.2%), and foot trauma (40.9% vs. 3.9%) were significantly more prevalent in cases compared to controls (p < 0.001 for all). Conclusions The significant associations observed with advanced age, uncontrolled diabetes, longer diabetes duration, neuropathy, and specific foot complications underscore the multifactorial nature of ulcer development. The normal levels of vitamin B12 in most patients reflect no positive impact of normalized vitamin B12 levels on DFU. However, further observational studies with multiple vitamin B12 readings over a longer period are needed to establish its association with DFU development.

Frailty in Diabetic Population: A Study From Northern India.

Introduction Frailty, a key issue in geriatric health, signifies heightened vulnerability due to the decline in various physiological systems, exacerbated by conditions such as diabetes. Diabetes and frailty together lead to significant disabilities and higher mortality, necessitating early screening and targeted interventions. The relationship between frailty and diabetes remains under-researched, prompting this study to explore their association in individuals over 50 years of age using the Edmonton Frail Scale (EFS). Methods and materials The study was an observational cross-sectional study conducted at MM Institute of Medical Sciences & Research (MMIMSR), Mullana, India, among 102 diabetic and 100 non-diabetic individuals aged more than 50 years, with data collected through interviews using a pre-validated proforma. Frailty was assessed using the EFS, categorizing patients into fit, vulnerable, and various levels of frailty based on their scores. Results The study found a higher prevalence and severity of frailty among diabetic individuals (61.8%) compared to non-diabetics (29%), with frailty being more pronounced across all age groups and both genders in diabetics. The severity of frailty increased with the duration of diabetes but showed no significant correlation with glycemic control (HbA1c). Strengths and limitations The study prospectively collected data, including middle-aged participants starting from age 50, and uniquely used the EFS to assess frailty in diabetic patients, excluding those with other chronic diseases (end-stage renal disease (ESRD), malignancy, etc.). However, limitations included a small sample size, recruitment from a single institution in India, and some EFS questions being less relevant to the Indian diabetic population. Conclusion The study found a 61.8% prevalence of frailty in diabetics compared to 29% in non-diabetics, with frailty being more severe and positively correlated with the duration of diabetes but not with glycemic control (HbA1c).

Expression of ten-eleven translocation 2 and glutathione-S-transferase pi in colorectal cancer patients with and without type 2 diabetes mellitus.

AIMS: To highlight possible correlations of type 2 diabetes mellitus (T2DM) with microscopic / macroscopic characteristics of colorectal cancer tissues, along with the expression of Ten-Eleven Translocation 2 (TET2) and glutathione-S-transferase pi (GST-pi) proteins.

Semaglutide exposure and its association with adverse outcomes in diabetic patients undergoing transforaminal lumbar interbody fusion for lumbar degenerative disc disease.

OBJECTIVE: Semaglutide, a novel glucagon-like peptide-1 receptor agonist, has transformed the therapeutic landscape for type 2 diabetes mellitus. However, its effect on osteoclast activity and its potential to induce weight-related muscle loss raises concerns about its impact on spine surgery outcomes. As such, evaluating semaglutide's influence on transforaminal lumbar interbody fusion (TLIF) is imperative, given the procedure's reliance on successful bony fusion to prevent postoperative instability and further interventions. METHODS: Using an all-payer database (MARINER), the authors analyzed data from patients with type 2 diabetes mellitus who were 18-74 years of age and who underwent short-segment fusion (≤ 3-level) TLIFs between January 2018 and October 2022. Patients were either exposed to semaglutide or not. A comprehensive 1:3 (exposure vs no exposure) matching was performed based on age, sex, obesity, hypertension, coronary artery disease, chronic kidney disease, smoking status, osteoporosis, levels of surgery, and basal-bolus insulin dependence. Kaplan-Meier survival curves and log-rank testing were performed to study the probability of additional lumbar fusion surgery within 1 year. RESULTS: After the 1:3 matching, 1781 patients were identified, with 447 in the semaglutide-exposed cohort and 1334 in the nonexposed cohort. Most patients in both groups were 55-69 years old, and 59.3% were female. Analysis showed that the likelihood of undergoing additional lumbar fusion surgery within 1 year post-TLIF was significantly higher in the semaglutide-exposed group than in the nonexposed group (OR 11.79, 95% CI 8.17-17.33). Kaplan-Meier plots and log-rank testing further confirmed a statistically significant divergent probability in the need for additional surgery within 1 year between the cohorts (log-rank, p < 0.001). CONCLUSIONS: Semaglutide exposure appears to be associated with a higher likelihood of additional lumbar fusion surgeries within 1 year post-TLIF, especially in patients receiving the medication for longer durations. Although the mechanisms remain speculative, potential impacts on bone turnover and the onset of muscle loss may be contributory factors. Further research is needed to elucidate the exact mechanisms and to develop strategies for optimizing surgical outcomes in these patients.

Photobiomodulation using red and infrared spectrum light emitting-diode (LED) for the healing of diabetic foot ulcers: a controlled randomized clinical trial.

Assessing the responses to the application of photobiomodulation using red and infrared spectrum light-emitting diodes (LED) on diabetic foot ulcers. Diabetic volunteers, of both genders, aged between 30 and 65 years, with grade I or II ulcers, were randomized into the groups: red LED, infrared LED, LED associated, and control. Home-based interventions took place on a daily basis for 12 weeks. Assessments of sample characterization were performed on day 1 and 90, and the variables wound healing index, mean skin temperature, sensitivity and pain in the wound area were measured at the pre-intervention time on days 1, 30, 60 and 90, with subsequent follow-up 30 days after the end of treatment. For statistical analysis, the software SPSS, version 17.0, intention-to-treat analysis, data normality was tested, and the linear mixed effects model, with a significance level of 5%. Magnitudes of clinical effect by Cohen's d. At the pre vs post intervention time of 90 days, we found a large clinical effect of G-LED V (d=1.7) and G -LED IV (d=1.6) in relation to G-C, where these intervention groups showed a tendency for faster wound healing compared to G-C. We also observed small clinical effect of G-LED IV, which showed greater reduction in the area in relation to G-LED V (d=0.4) and G-LED A (d=0.3). Conclusion: The use of individually applied red and infrared LED phototherapy clinically tended to be more effective for the reduction of diabetic foot ulcer areas, and infrared LED was the most effective. Trial registration: NCT03250533 (clinicaltrials.gov).

Novel insights into the genetic architecture of pregnancy glycemic traits from 14,744 Chinese maternities.

Glycemic traits are critical indicators of maternal and fetal health during pregnancy. We performed genetic analysis for five glycemic traits in 14,744 Chinese pregnant women. Our genome-wide association study identified 25 locus-trait associations, including established links between gestational diabetes mellitus (GDM) and the genes CDKAL1 and MTNR1B. Notably, we discovered a novel association between fasting glucose during pregnancy and the ESR1 gene (estrogen receptor), which was validated by an independent study in pregnant women. The ESR1-GDM link was recently reported by the FinnGen project. Our work enhances the findings in East Asian populations and highlights the need for independent studies. Further analyses, including genetic correlation, Mendelian randomization, and transcriptome-wide association studies, provided genetic insights into the relationship between pregnancy glycemic traits and hypertension. Overall, our findings advance the understanding of genetic architecture of pregnancy glycemic traits, especially in East Asian populations.

Role of toll-like receptor 4/mutant myeloid differentiation primary response 88/nuclear factor kappa-B mediated inflammation in diabetes mellitus with Northwest dryness syndrome.

OBJECTIVE: To investigate the role of toll-like receptor 4 (TLR4)/mutant myeloid differentiation primary response 88 (MyD88)/nuclear factor kappa-B (NF-κB) signaling pathway-mediated inflammation in diabetes mellitus with Northwest dryness syndrome. METHODS: Rats were randomly divided into the normal control, type 2 diabetes (T2DM) model, Northwest dryness syndrome + T2DM (Northwest dryness), and simple internal dampness + T2DM (internal dampness) groups. Enzyme-linked immunosorbent assay was used to detect biochemical indexes and inflammatory factors. The histopathological observation was performed. Quantitative real-time polymerase chain reaction and Western blot analysis were used to detect the mRNA and protein expression levels, respectively. RESULTS: Compared with the T2DM group, the glycosylated hemoglobin A1c, insulin, glucose tolerance, the homeostasis model assessment of insulin resistance, tumor necrosis factor-α, interleukin 1ß, interleukin 16, malondialdehyde, blood lipid, alanine aminotransferase, and aspartate aminotransferase were significantly elevated in the internal dampness group. Their levels were significantly elevated in the Northwest dryness group than in the T2DM and internal dampness groups. The superoxide dismutase, glutathione peroxidase, liver glycogen, and organ-to-weight ratio were significantly declined in the internal dampness group and the Northwest dryness group than in the T2DM group. However, these levels were elevated in the Northwest dryness group than in the internal dampness group. Moreover, the mRNA expression levels of interferon regulatory factor 5 and NF-κB p65, and the protein expression levels of TLR4, MyD88, and NF-κB were significantly higher in the internal dampness and the Northwest dryness groups than the T2DM group. Additionally, the mRNA and protein levels were significantly higher in the Northwest dryness group than in the internal dampness group. CONCLUSION: Northwest dryness syndrome-mediated TLR4/MyD88/NF-κB pathway and chronic inflammation might be associated with the occurrence and development of T2DM.

Association between incretin-based drugs and risk of cholangiocarcinoma among patients with type 2 diabetes: A large population-based matched cohort study.

Aim: To examine the association between the use of incretin-based drugs [glucagon-like peptide-1 receptor agonists (GLP-1RAs), dipeptidyl peptidase-4 inhibitors (DPP-4Is)] and the risk of cholangiocarcinoma (CCA) in the United States. Methods: This large population-based, retrospective cohort study using the TriNetX datasets included adult patients with type 2 diabetes mellitus (T2DM) who were new users of GLP-1RAs, DPP-4Is, or other second- or third-line antidiabetic drugs between 2010 and 2021. The primary outcome was the incidence of CCA. Results: A total of 3,816,071 patients were included (mean age, 61.4 years, female, 49.3 %). A 51 % and 23 % risk reduction in CCA after 1 year of exposure to GLP-1RAs (hazard ratio 0.49; 95 % CI 0.40-0.60) and DPP4Is (0.77, 95 % CI 0.67-0.90), respectively compared to new second-or third-line users. Results were consistent at 3, 5, and 7 years of follow-up (0.66, 0.71, and 0.72 for GLP-1RAs and 0.84, 0.87, and 0.85 for DPP-4Is, respectively). Compared to new metformin users, GLP-1RA users were associated with a 42 % lower risk of developing CCA, whereas DPP-4I group was not associated with an increased risk. Conclusions: GLP-1RAs and DPP-4Is were not associated with a significantly increased risk of CCA. GLP-1RAs even showed a reduced risk of CCA development. They can be considered as safe and effective treatment options for patients with T2DM at risk of CCA.