Continuous glucose monitoring with structured education in adults with type 2 diabetes managed by multiple daily insulin injections: a multicentre randomised controlled trial.

AIMS/HYPOTHESIS: The aim of this study was to compare the effectiveness of stand-alone intermittently scanned continuous glucose monitoring (isCGM) with or without a structured education programme and blood glucose monitoring (BGM) in adults with type 2 diabetes on multiple daily insulin injections (MDI). METHODS: In this 24 week randomised open-label multicentre trial, adults with type 2 diabetes on intensive insulin therapy with HbA1c levels of 58-108 mmol/mol (7.5-12.0%) were randomly assigned in a 1:1:1 ratio to isCGM with a structured education programme on adjusting insulin dose and timing according to graphical patterns in CGM (intervention group), isCGM with conventional education (control group 1) or BGM with conventional education (control group 2). Block randomisation was conducted by an independent statistician. Due to the nature of the intervention, blinding of participants and investigators was not possible. The primary outcome was change in HbA1c from baseline at 24 weeks, assessed using ANCOVA with the baseline value as a covariate. RESULTS: A total of 159 individuals were randomised (n=53 for each group); 148 were included in the full analysis set, with 52 in the intervention group, 49 in control group 1 and 47 in control group 2. The mean (± SD) HbA1c level at baseline was 68.19±10.94 mmol/mol (8.39±1.00%). The least squares mean change (± SEM) from baseline HbA1c at 24 weeks was -10.96±1.35 mmol/mol (-1.00±0.12%) in the intervention group, -6.87±1.39 mmol/mol (-0.63±0.13%) in control group 1 (p=0.0367 vs intervention group) and -6.32±1.42 mmol/mol (-0.58±0.13%) in control group 2 (p=0.0193 vs intervention group). Adverse events occurred in 28.85% (15/52) of individuals in the intervention group, 26.42% (14/53) in control group 1 and 48.08% (25/52) in control group 2. CONCLUSIONS/INTERPRETATION: Stand-alone isCGM offers a greater reduction in HbA1c in adults with type 2 diabetes on MDI when education on the interpretation of graphical patterns in CGM is provided. TRIAL REGISTRATION: ClinicalTrials.gov NCT04926623. FUNDING: This study was supported by Daewoong Pharmaceutical Co., Ltd.

Comparison between a tubeless, on-body automated insulin delivery system and a tubeless, on-body sensor-augmented pump in type 1 diabetes: a multicentre randomised controlled trial.

AIMS/HYPOTHESIS: This study compares the efficacy and safety of a tubeless, on-body automated insulin delivery (AID) system with that of a tubeless, on-body sensor-augmented pump (SAP). METHODS: This multicentre, parallel-group, RCT was conducted at 13 tertiary medical centres in South Korea. Adults aged 19-69 years with type 1 diabetes who had HbA1c levels of <85.8 mmol/mol (<10.0%) were eligible. The participants were assigned at a 1:1 ratio to receive a tubeless, on-body AID system (intervention group) or a tubeless, on-body SAP (control group) for 12 weeks. Stratified block randomisation was conducted by an independent statistician. Blinding was not possible due to the nature of the intervention. The primary outcome was the percentage of time in range (TIR), blood glucose between 3.9 and 10.0 mmol/l, as measured by continuous glucose monitoring. ANCOVAs were conducted with baseline values and study centres as covariates. RESULTS: A total of 104 participants underwent randomisation, with 53 in the intervention group and 51 in the control group. The mean (±SD) age of the participants was 40±11 years. The mean (±SD) TIR increased from 62.1±17.1% at baseline to 71.5±10.7% over the 12 week trial period in the intervention group and from 64.7±17.0% to 66.9±15.0% in the control group (difference between the adjusted means: 6.5% [95% CI 3.6%, 9.4%], p<0.001). Time below range, time above range, CV and mean glucose levels were also significantly better in the intervention group compared with the control group. HbA1c decreased from 50.9±9.9 mmol/mol (6.8±0.9%) at baseline to 45.9±7.4 mmol/mol (6.4±0.7%) after 12 weeks in the intervention group and from 48.7±9.1 mmol/mol (6.6±0.8%) to 45.7±7.5 mmol/mol (6.3±0.7%) in the control group (difference between the adjusted means: -0.7 mmol/mol [95% CI -2.0, 0.8 mmol/mol] (-0.1% [95% CI -0.2%, 0.1%]), p=0.366). No diabetic ketoacidosis or severe hypoglycaemia events occurred in either group. CONCLUSIONS/INTERPRETATION: The use of a tubeless, on-body AID system was safe and associated with superior glycaemic profiles, including TIR, time below range, time above range and CV, than the use of a tubeless, on-body SAP. TRIAL REGISTRATION: Clinical Research Information Service (CRIS) KCT0008398 FUNDING: The study was funded by a grant from the Korea Medical Device Development Fund supported by the Ministry of Science and ICT; the Ministry of Trade, Industry and Energy; the Ministry of Health and Welfare; and the Ministry of Food and Drug Safety (grant number: RS-2020-KD000056).

Efficacy and tolerability of initial triple combination therapy with metformin, dapagliflozin and saxagliptin compared with stepwise add-on therapy in drug-naïve patients with type 2 diabetes (TRIPLE-AXEL study): A multicentre, randomized, 104-week, open-label, active-controlled trial.

AIM: To evaluate the efficacy and tolerability of an initial triple combination therapy (TCT) compared with conventional stepwise add-on therapy (SAT) in patients with newly diagnosed type 2 diabetes (T2D). MATERIALS AND METHODS: This multicentre, randomized, 104-week, open-label trial randomized 105 patients with drug-naïve T2D (with HbA1c level ≥ 8.0%, < 11.0%) to the TCT (1000 mg of metformin, 10 mg of dapagliflozin and 5 mg of saxagliptin once daily) or SAT (initiated with metformin, followed by glimepiride and sitagliptin) groups. The primary outcome was the proportion of patients who achieved an HbA1c level of less than 6.5% without hypoglycaemia, weight gain of 5% or higher, or discontinuation of drugs because of adverse events at week 104. RESULTS: HbA1c reduction from baseline at week 104 was similar between the groups (the least squares mean change was -2.56% in the TCT group vs. -2.75% in the SAT group). The primary outcome was achieved in 39.0% and 17.1% of the TCT and SAT groups, respectively, with a risk difference of 22.0 (95% confidence interval 3.0, 40.8; P = .027). HbA1c level less than 6.5% at week 104 was 46.3% in both the TCT and SAT groups, whereas the incidence of hypoglycaemia, weight gain, or discontinuation of drugs was 16.7% and 62.0% in the TCT and SAT groups, respectively (P < .001). TCT was well-tolerated and had fewer adverse events than SAT. CONCLUSIONS: Among newly diagnosed patients with T2D, initial TCT effectively lowered HbA1c levels with higher tolerability and safety than SAT for 104 weeks, suggesting a novel strategy for initial combination therapy in T2D patients.

Noncontact Sensors for Vital Signs Measurement: A Narrative Review.

Vital signs are crucial for monitoring changes in patient health status. This review compared the performance of noncontact sensors with traditional methods for measuring vital signs and investigated the clinical feasibility of noncontact sensors for medical use. We searched the Medical Literature Analysis and Retrieval System Online (MEDLINE) database for articles published through September 30, 2023, and used the key search terms "vital sign," "monitoring," and "sensor" to identify relevant articles. We included studies that measured vital signs using traditional methods and noncontact sensors and excluded articles not written in English, case reports, reviews, and conference presentations. In total, 129 studies were identified, and eligible articles were selected based on their titles, abstracts, and full texts. Three articles were finally included in the review, and the types of noncontact sensors used in each selected study were an impulse radio ultrawideband radar, a microbend fiber-optic sensor, and a mat-type air pressure sensor. Participants included neonates in the neonatal intensive care unit, patients with sleep apnea, and patients with coronavirus disease. Their heart rate, respiratory rate, blood pressure, body temperature, and arterial oxygen saturation were measured. Studies have demonstrated that the performance of noncontact sensors is comparable to that of traditional methods of vital signs measurement. Noncontact sensors have the potential to alleviate concerns related to skin disorders associated with traditional skin-contact vital signs measurement methods, reduce the workload for healthcare providers, and enhance patient comfort. This article reviews the medical use of noncontact sensors for measuring vital signs and aimed to determine their potential clinical applicability.

Comparison of the effects of gemigliptin versus glimepiride on cardiac function in patients with type 2 diabetes uncontrolled with metformin: The gemi-heart study.

AIM: To investigate the effects of gemigliptin on cardiac function and compare the effects of gemigliptin and glimepiride in patients with type 2 diabetes (T2D). MATERIALS AND METHODS: Sixty T2D patients being treated with metformin were assigned to a gemigliptin group (50 mg daily) or a glimepiride group (2 mg daily) for 24 weeks. The preadjudicated extension period was up to 52 weeks. Glucose metabolism variables and cardiac biomarkers were measured. Echocardiography was used to evaluate cardiac functions. RESULTS: The HbA1c levels decreased significantly from 8.1% ± 0.6% to 6.8% ± 0.6% in the gemigliptin group and from 8.1% ± 0.6% to 7.0% ± 0.7% in the glimepiride group, without a between-group difference. Gemigliptin reduced insulin resistance, high sensitivity C-reactive protein and low-density lipoprotein cholesterol levels, and blood pressure, and increased adiponectin level compared with glimepiride therapy. Gemigliptin induced favourable changes in body composition. Left ventricular end-diastolic volume decreased in the gemigliptin group but increased in the glimepiride group, with a borderline between-group difference. Cardiac biomarkers did not change significantly in either group. At 52 weeks, the HbA1c levels in both groups increased slightly; 7.3% ± 0.8% in the gemigliptin group versus 7.7% ± 1.3% in the glimepiride group, without a between-group difference. CONCLUSIONS: Gemigliptin had a comparable glucose-lowering efficacy without deleterious effects on cardiac functions or on biomarkers reflective of myocardial injury or heart failure during the 24-week observation period. However, larger, longer-term studies are needed to confirm these findings.

Medial Arterial Calcification and the Risk of Amputation of Diabetic Foot Ulcer in Patients With Diabetic Kidney Disease.

We assessed the risk factors for major amputation of diabetic foot ulcers (DFUs) in patients with diabetic kidney disease (DKD) stages 3b-5. For DFU assessment, in addition to DFU location and presence of infection, ischemia, and neuropathy, vascular calcification was assessed using the medial arterial calcification (MAC) score. Of 210 patients, 26 (12.4%) underwent major amputations. Only the location and extension of DFU, represented by Texas grade differed between the minor and major amputation groups. However, after adjusting for covariates, ulcer location of mid- or hindfoot (vs. forefoot, odds ratio [OR] = 3.27), Texas grades 2 or 3 (vs. grade 0, OR = 5.78), and severe MAC (vs. no MAC, OR = 4.46) was an independent risk factor for major amputation (all P < 0.05). The current use of antiplatelets was a possible protective factor for major amputations (OR = 0.37, P = 0.055). In conclusion, DFU with severe MAC is associated with major amputation in patients with DKD.

Perfluorinated compounds in adults and their association with fasting glucose and incident diabetes: a prospective cohort study.

BACKGROUND: The endocrine disruption of perfluorinated compounds is an emerging issue. We aimed to examine the association of serum perfluorooctanoic acid (PFOA) and perfluorooctanesulfonic acid (PFOS) levels with incident diabetes and fasting serum glucose concentration. METHODS: This prospective cohort study was based on an urban-based cohort subpopulation from the Korean Genome and Epidemiology Study. Serum samples (600 µL) were received from 100 participants in the normoglycemic baseline survey (2004-2013), and concentrations of PFOA and PFOS were measured using mass spectrometry. The incidence of diabetes was tracked in the follow-up survey (2012-2016). RESULTS: The mean age was 56.4 years (men, 59%). The median serum PFOA and PFOS concentrations were 4.29 ng/mL and 9.44 ng/mL, respectively. PFOA and PFOS concentrations differed according to age, sex, and residential area. After 60 months, 23 patients had diabetes. Log-transformed PFOA (lnPFOA) and log-transformed PFOS (lnPFOS) were significantly higher in those who transitioned to diabetes than in those who did not (both p < 0.05). After multivariate adjustment, lnPFOA (coefficient = 6.98, 95% CI -0.04-14, p = 0.054) and lnPFOS (coefficient = 7.06, 95% CI -0.96-15.08, p = 0.088) predicted increased fasting glucose without statistical significance. In addition, lnPFOA, but not lnPFOS, significantly predicted incident diabetes (HR = 3.98, 95% CI 1.42-11.1, p < 0.01). CONCLUSION: Exposure to PFOA and PFOS may have a potential dysglycemic effect. In particular, exposure to PFOA increased the risk of diabetes. Further research with larger sample size is warranted.

Ferroptosis Signaling in Pancreatic ß-Cells: Novel Insights & Therapeutic Targeting.

Metabolic stress impairs pancreatic ß-cell survival and function in diabetes. Although the pathophysiology of metabolic stress is complex, aberrant tissue damage and ß-cell death are brought on by an imbalance in redox equilibrium due to insufficient levels of endogenous antioxidant expression in ß-cells. The vulnerability of ß-cells to oxidative damage caused by iron accumulation has been linked to contributory ß-cell ferroptotic-like malfunction under diabetogenic settings. Here, we take into account recent findings on how iron metabolism contributes to the deregulation of the redox response in diabetic conditions as well as the ferroptotic-like malfunction in the pancreatic ß-cells, which may offer insights for deciphering the pathomechanisms and formulating plans for the treatment or prevention of metabolic stress brought on by ß-cell failure.

Daytime Glycemic Variability and Frailty in Older Patients with Diabetes: a Pilot Study Using Continuous Glucose Monitoring.

We investigated the relationship between glucose variability and frailty. Forty-eight type 2 diabetic patients aged ≥ 65 years were enrolled. The FRAIL scale was used for frailty assessment, and participants were classified into 'healthy & pre-frail' (n = 24) and 'frail' (n = 24) groups. A continuous glucose monitoring (CGM) system was used for a mean of 6.9 days and standardized CGM metrics were analyzed: mean glucose, glucose management indicator (GMI), coefficient of variation, and time in range, time above range (TAR), and time below range. The demographics did not differ between groups. However, among the CGM metrics, mean glucose, GMI, and TAR in the postprandial periods were higher in the frail group (all P < 0.05). After multivariate adjustments, the post-lunch TAR (OR = 1.12, P = 0.019) affected the prevalence of frailty. Higher glucose variability with marked daytime postprandial hyperglycemia is significantly associated with frailty in older patients with diabetes.

CD36 initiated signaling mediates ceramide-induced TXNIP expression in pancreatic beta-cells.

Diverse mechanisms are involved in the pathogenesis of ß-cell failure in type 2 diabetes. Of them, the accumulation of ceramide, a bioactive lipid metabolite, is suggested to play a major role in inflammatory and stress responses that induce diabetes. However, the downstream inflammatory target of ceramide has not been defined. Using rat islets and the INS-1 ß-cell line, we hypothesized that activation of the redox sensitive protein TXNIP is involved in ceramide-induced ß-cell dysfunction. Incubation of INS-1 cells and primary islets with C2-ceramide (N-acetyl-sphingosine) downregulated insulin and PDX-1 expression and increased ß-cell apoptosis. Ceramide treatment induced a time dependent increase in TXNIP gene expression accompanied by activation of nuclear factor (NF)-κB and reduced mitochondrial thioredoxin (TRX) activity. Pretreatment with sulfo-N-succinimidyl oleate (SSO), an irreversible inhibitor of the scavenger receptor CD36, blocked ceramide-induced up-regulation of TXNIP expression and activity of NF-κB. Blockade of NF-κB nuclear translocation by the peptide SN50 prevented ceramide-mediated TXNIP induction. Furthermore, SSO also attenuated ceramide-induced early loss of insulin signaling and apoptosis. Collectively, our results unveil a novel role of CD36 in early molecular events leading to NF-κB activation and TXNIP expression. These data suggest that CD36 dependent NF-κB-TXNIP signaling contributes to the ceramide-induced pathogenesis of pancreatic ß-cell dysfunction and failure.

The Glucotoxicity Protecting Effect of Ezetimibe in Pancreatic Beta Cells via Inhibition of CD36.

Inhibition of CD36, a fatty acid transporter, has been reported to prevent glucotoxicity and ameliorate high glucose induced beta cell dysfunction. Ezetimibe is a selective cholesterol absorption inhibitor that blocks Niemann Pick C1-like 1 protein, but may exert its effect through suppression of CD36. We attempted to clarify the beneficial effect of ezetimibe on insulin secreting cells and to determine whether this effect is related to change of CD36 expression. mRNA expression of insulin and CD36, intracellular peroxide level and glucose stimulated insulin secretion (GSIS) under normal (5.6 mM) or high glucose (30 mM) condition in INS-1 cells and primary rat islet cells were compared. Changes of the aforementioned factors with treatment with ezetimibe (20 µM) under normal or high glucose condition were also assessed. mRNA expression of insulin was decreased with high glucose, which was reversed by ezetimibe in both INS-1 cells and primary rat islets. CD36 mRNA expression was increased with high glucose, but decreased by ezetimibe in INS-1 cells and primary rat islets. Three-day treatment with high glucose resulted in an increase in intracellular peroxide level; however, it was decreased by treatment with ezetimibe. Decrease in GSIS by three-day treatment with high glucose was reversed by ezetimibe. Palmitate uptake following exposure to high glucose conditions for three days was significantly elevated, which was reversed by ezetimibe in INS-1 cells. Ezetimibe may prevent glucotoxicity in pancreatic ß-cells through a decrease in fatty acid influx via inhibition of CD36.

Relationship between bone mineral density, its associated physiological factors, and tooth loss in postmenopausal Korean women.

BACKGROUND: Previous studies have proposed a relationship between bone mineral density (BMD) and oral health. However, the relationship between BMD and tooth loss in female individuals is not yet well understood. Therefore, the aim of this study was to assess the association between BMD, including its related physiological factors, and tooth loss among postmenopausal women in Korea. METHODS: A total of 3,992 postmenopausal women aged 50 years or above were selected from the Fourth and Fifth Korea National Health and Nutrition Examination Surveys, which were cross-sectional in design and conducted from 2008 to 2011. The participants' BMD and number of teeth were assessed by radiologists and dentists. Socioeconomic characteristics and female-related physiological factors, including menarche age, duration of menopause, number of pregnancies, age at first child's birth, and duration of oral contraceptive or female hormone use, were surveyed. RESULTS: Participants who had lower BMD had significantly fewer teeth (p < 0.001). Female-related physiological factors, including the duration of menopause, number of pregnancies, age at first child's birth, duration of oral contraceptive or female hormone use, and calcium intake level, showed a significant relationship with the number of teeth. Using multiple regression analysis, BMD, duration of menopause, age at first child's birth, and duration of female hormone use significantly influenced the number of teeth. CONCLUSIONS: BMD and its related physiological factors in female individuals showed a significant relationship with the number of teeth in postmenopausal Korean women, implicating osteoporosis as a risk factor for tooth loss in postmenopausal women.

Application of non-contact sensors for health monitoring in hospitals: a narrative review.

The continuous monitoring of the health status of patients is essential for the effective monitoring of disease progression and the management of symptoms. Recently, health monitoring using non-contact sensors has gained interest. Therefore, this study aimed to investigate the use of non-contact sensors for health monitoring in hospital settings and evaluate their potential clinical applications. A comprehensive literature search was conducted using PubMed to identify relevant studies published up to February 26, 2024. The search terms included "hospital," "monitoring," "sensor," and "non-contact." Studies that used non-contact sensors to monitor health status in hospital settings were included in this review. Of the 38 search results, five studies met the inclusion criteria. The non-contact sensors described in the studies were radar, infrared, and microwave sensors. These non-contact sensors were used to obtain vital signs, such as respiratory rate, heart rate, and body temperature, and were then compared with the results from conventional measurement methods (polysomnography, nursing records, and electrocardiography). In all the included studies, non-contact sensors demonstrated a performance similar to that of conventional health-related parameter measurement methods. Non-contact sensors are expected to be a promising solution for health monitoring in hospital settings.

Association between mixed exposure to per- and polyfluoroalkyl substances and metabolic syndrome in Korean adults: Data from the Korean National environmental health survey cycle 4.

AIM: To explore the effect of mixed exposure to per- and polyfluoroalkyl substances (PFAS) on metabolic syndrome (MetS). METHODS: This cross-sectional study used data from the Korean National Environmental Health Survey Cycle 4 (2018-2020). The serum concentrations of five PFAS (perfluorooctanoic acid [PFOA], perfluorooctanesulfonic acid [PFOS], perfluorohexanesulfonic acid, perfluorononanoic acid [PFNA], and perfluorodecanoic acid [PFDeA]) were measured, and the relative potency factor approach was employed for the mixture of PFAS (Cmix) assessment. MetS was diagnosed if the patient satisfied three of five criteria: central obesity, elevated triglycerides, reduced high-density lipoprotein cholesterol, elevated blood pressure (BP), and elevated glycated hemoglobin (HbA1c). Age, sex, smoking, drinking, and exercise status were considered as covariates. The risk of MetS for single and mixed exposure to PFAS was analyzed using binomial regression and Bayesian kernel machine regression (BKMR). RESULTS: A total of 2984 (male:female = 1:1.3; age range, 19-80 years) adults were enrolled. The prevalence of MetS was 45.6%. Each PFAS and Cmix levels were higher in participants with MetS than in those without MetS. Cmix increased the risk of elevated BP and HbA1c, and eventually MetS (odds ratio [OR] = 2.00, 95% confidence interval [CI] 1.11-3.60 per log10Cmix; OR = 1.57, 95% CI 1.07-2.31 in the highest quartile of Cmix [Q4] vs. the lowest [Q1]). Sex-specific analyses revealed that the impact of Cmix was valid in females but not in males (Cmix Q4 vs. Q1: OR = 1.01, 95% CI 0.57-1.8 in males; OR = 2.30, 95% CI 1.38-3.84 in females). In the BKMR analysis, mixed exposure to PFAS dose-dependently increased the risk of MetS, particularly in females. Among single exposures, PFNA contributed significantly to the cumulative effect. CONCLUSION: Mixed exposure to PFAS was associated with a higher risk of MetS in females. Further studies on potential health concerns associated with PFAS mixtures are warranted.

The applicability of noncontact sensors in the field of rehabilitation medicine.

A noncontact sensor field is an innovative device that can detect, measure, or monitor physical properties or conditions without direct physical contact with the subject or object under examination. These sensors use a variety of methods, including electromagnetic, optical, and acoustic technique, to collect information about the target without physical interaction. Noncontact sensors find wide-ranging applications in various fields such as manufacturing, robotics, automobiles, security, environmental monitoring, space industry, agriculture, and entertainment. In particular, they are used in the medical field, where they provide continuous monitoring of patient conditions and offer opportunities in rehabilitation medicine. This article introduces the potential of noncontact sensors in the field of rehabilitation medicine.

Mitochondrial ALDH2 improves ß-cell survival and function against doxorubicin-induced apoptosis by targeting CK2 signaling.

AIMS: The aim of this study was to better understand how the chemotherapy drug doxorubicin contributes to the development of ß-cell dysfunction and to explore its relationship with mitochondrial aldehyde dehydrogenase-2 (ALDH2). MATERIALS AND METHODS: In order to investigate this hypothesis, doxorubicin was administered to INS-1 cells, a rat insulinoma cell line, either with or without several target protein activators and inhibitors. ALDH2 activity was detected with a commercial kit and protein levels were determined with western blot. Mitochondrial ROS, membrane potential, and lipid ROS were determined by commercial fluorescent probes. The cell viability was measured by CCK-assay. RESULTS: Exposure of INS-1 cells to doxorubicin decreased active insulin signaling resulting in elevated ALDH2 degradation, compared with control cells by the induction of acid sphingomyelinase mediated ceramide induction. Further, ceramide induction potentiated doxorubicin induced mitochondrial dysfunction. Treatment with the ALDH2 agonist, ALDA1, blocked doxorubicin-induced acid sphingomyelinase activation which significantly blocked ceramide induction and mitochondrial dysfunction mediated cell death. Treatment with the ALDH2 agonist, ALDA1, stimulated casein kinase-2 (CK2) mediated insulin signaling activation. CK2 silencing neutralized the function of ALDH2 in the doxorubicin treated INS-1 cells. CONCLUSIONS: Mitochondrial ALDH2 activation could inhibit the progression of doxorubicin induced pancreatic ß-cell dysfunction by inhibiting the acid sphingomyelinase induction of ceramide, by regulating the activation of CK2 signaling. Our research lays the foundation of ALDH2 activation as a therapeutic target for the precise treatment of chemotherapy drug induced ß-cell dysfunction.

Mitochondrial aldehyde dehydrogenase-2 coordinates the hydrogen sulfide - AMPK axis to attenuate high glucose-induced pancreatic ß-cell dysfunction by glutathione antioxidant system.

Progression of ß-cell loss in diabetes mellitus is significantly influenced by persistent hyperglycemia. At the cellular level, a number of signaling cascades affect the expression of apoptotic genes, ultimately resulting in ß-cell failure; these cascades have not been elucidated. Mitochondrial aldehyde dehydrogenase-2 (ALDH2) plays a central role in the detoxification of reactive aldehydes generated from endogenous and exogenous sources and protects against mitochondrial deterioration in cells. Here we report that under diabetogenic conditions, ALDH2 is strongly inactivated in ß-cells through CDK5-dependent glutathione antioxidant imbalance by glucose-6-phosphate dehydrogenase (G6PD) degradation. Intriguingly, CDK5 inhibition strengthens mitochondrial antioxidant defense through ALDH2 activation. Mitochondrial ALDH2 activation selectively preserves ß-cells against high-glucose-induced dysfunction by activating AMPK and Hydrogen Sulfide (H2S) signaling. This is associated with the stabilization and enhancement of the activity of G6PD by SIRT2, a cytoplasmic NAD+-dependent deacetylase, and is thereby linked to an elevation in the GSH/GSSG ratio, which leads to the inhibition of mitochondrial dysfunction under high-glucose conditions. Furthermore, treatment with NaHS, an H2S donor, selectively preserves ß-cell function by promoting ALDH2 activity, leading to the inhibition of lipid peroxidation by high-glucose concentrations. Collectively, our results provide the first direct evidence that ALDH2 activation enhances H2S-AMPK-G6PD signaling, leading to improved ß-cell function and survival under high-glucose conditions via the glutathione redox balance.

Impact of Chronic Kidney Disease and Gout on End-Stage Renal Disease in Type 2 Diabetes: Population-Based Cohort Study.

Background: We examined the impact of gout on the end-stage renal disease (ESRD) risk in patients with type 2 diabetes mellitus (T2DM) and determined whether this association differs according to chronic kidney disease (CKD) status. Methods: Using the Korean National Health Insurance Service, this nationwide cohort study enrolled 847,884 patients with T2DM who underwent health checkups in 2009. Based on the presence of CKD (estimated glomerular filtration rate <60 mL/min/1.73 m2) and gout (two outpatient visits or one hospitalization within 5 years), patients were classified into four groups: CKD-Gout-, CKD- Gout+, CKD+Gout-, and CKD+Gout+. Patients with incident ESRD were followed up until December 2018. Results: Among 847,884 patients, 11,825 (1.4%) experienced progression to ESRD. ESRD incidence increased in the following order: 0.77 per 1,000 person-years (PY) in the CKD-Gout- group, 1.34/1,000 PY in the CKD-Gout+ group, 8.20/1,000 PY in the CKD+Gout- group, and 23.06/1,000 PY in the CKD+Gout+ group. The presence of gout modified the ESRD risk in a status-dependent manner. Hazard ratios (HR) were 1.49 (95% confidence interval [CI], 1.32 to 1.69) and 2.24 (95% CI, 2.09 to 2.40) in patients without and with CKD, respectively, indicating a significant interaction (P<0.0001). The CKD+Gout+ group had a markedly higher risk of developing ESRD (HR, 18.9; 95% CI, 17.58 to 20.32) than the reference group (CKD-Gout-). Conclusion: Gout substantially enhances the risk of ESRD, even in the absence of CKD. Concurrent CKD and gout synergistically increase the risk of ESRD. Therefore, physicians should carefully screen for hyperuricemia to prevent progression to ESRD.

Effect of gout and diabetic kidney disease on renal cancer development in Korea.

Background: Chronic kidney disease (CKD) and gout are risk factors for renal cancer. We analysed the effects of comorbid diabetic kidney disease and gout on renal cancer. Methods: This retrospective cohort study enrolled 847 884 patients with type 2 diabetes mellitus (T2DM) who underwent health assessments provided by the Korean National Health Insurance Service in 2009. Based on CKD occurrence (glomerular filtration rate <60 ml/min/1.73 m2) and gout (two outpatient visits or one hospitalization within 5 years), patients were classified into four groups: CKD-Gout- (87.5%), CKD-Gout+ (2.5%), CKD+Gout- (9.3%) and CKD+Gout+ (0.7%). Patients with incident renal cancer (International Classification of Diseases code C64) were followed up until December 2018. Results: Renal cancer was diagnosed in 2376 patients (0.3%). Renal cancer incidence increased in sequential order of CKD-Gout- [0.29/1000 person-years (PY), CKD+Gout- and CKD-Gout+ (0.44 and 0.48/1000 PY, respectively) and CKD+Gout+ (1.14/1000 PY). Comorbid gout increased renal cancer risk depending on CKD occurrence {hazard ratio [HR] 1.28 [95% confidence interval (CI) 1.04-1.58 among those without CKD; HR 1.95 [95% CI 1.45-2.63] among those with CKD; P-value for interaction = 0.024}. The interaction was significant, particularly in men and patients with a shorter diabetes duration (<5 years) and lesser medication use (no insulin or fewer than three classes of oral hypoglycaemic agents). Conclusions: CKD and gout individually contributed to renal cancer incidence, and the risk is further increased when gout coexists with CKD. Screening for gout and appropriate management of CKD at an early T2DM stage may be beneficial.

The Potential Role of Presepsin in Predicting Severe Infection in Patients with Diabetic Foot Ulcers.

Background/Objectives: Diabetic foot ulcers are one of the complications in patients with diabetes, which can be caused by infection, neuropathy, and blood vessel disorder. Among them, infection is the most common cause, and if it becomes worse, amputation may be necessary. So, it is important to detect and treat infections early, and determining indicators that can confirm infection is also important. Known infection markers include white blood cells (WBCs), the erythrocyte sediment rate (ESR), C-reactive protein (CRP), and procalcitonin, but they are not specific to diabetic foot ulcers. Presepsin, also known as soluble CD14, is known to be an early indicator of sepsis. Recent studies have reported that presepsin can be used as an early indicator of infection. This study investigated whether presepsin could be used as an early marker of severe infection in patients with diabetic foot ulcers. Methods: We retrospectively studied 73 patients who were treated for diabetic foot ulcerations from January 2021 to June 2023 at Yeungnam University Hospital. Results: Out of a total of 73 patients, 46 patients underwent amputations with severe infections, and the WBC level, ESR, and CRP, procalcitonin, and presepsin levels were significantly higher in the group of patients who underwent amputations. The cutoff of presepsin, which can predict serious infections that need amputation, was 675 ng/mL. A regression analysis confirmed that presepsin, HbA1c, and osteomyelitis significantly increased the risk of severe infections requiring amputation. Conclusions: Presepsin will be available as an early predictor of patients with severe infections requiring amputations for diabetic foot ulcerations.