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.

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.

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.

Early glycaemic variability increases 28-day mortality and prolongs intensive care unit stay in critically ill patients with pneumonia.

OBJECTIVE: This study aimed to evaluate the effect of early glycaemic variability (GV) on 28-day mortality in critically ill patients with pneumonia. PATIENTS AND METHODS: This single-centre retrospective study included patients admitted to the intensive care unit (ICU) due to pneumonia between 2018 and 2019. A total of 282 patients (mean age, 68.6 years) with blood sugar test (BST) results measured more than three times within 48 h after hospitalization and haemoglobin A1c (HbA1c) levels recorded within 2 months were enrolled. Coefficient of variation (CV) was calculated using the BST values. The effects of GV on 28-day mortality and prolonged ICU stay (>14 days) were also assessed. RESULTS: The mean age was 60.6 years (male to female ratio, 2.5:1). The 28-day mortality rate was 31.6% (n = 89) and was not different according to the presence of diabetes (DM vs. non-DM) or HbA1c levels (≥7.5 vs. <7.5%; both p > .05). However, the mortality rate was significantly higher in patients with high GV (CV ≥ 36%) than in those with low GV (CV < 36%; 37.5 vs. 25.4%, p = .028). The risk of mortality in patients with high GV was prominent in the subgroups with DM or low HbA1c levels. Among the surviving patients (n = 193), 44 remained in the ICU for more than 14 days. Compared to low GV, high GV was associated with a higher rate of prolonged ICU stay, although not statistically significant (27.8 vs. 18.5%, p = .171). After adjusting for the severity of illness and treatment strategy, CV was an independent risk factor for 28-day mortality (hazard ratio [HR], 1.01, p = .04) and prolonged ICU stay (odds ratio, 1.02; p = .04). CONCLUSIONS: High GV within 48 h of ICU admission was associated with an increased 28-day mortality risk and prolonged ICU stay. Early phase GV should be carefully managed in critically ill patients with pneumonia.KEY MESSAGESThe presence of diabetes or HbA1c alone is insufficient to predict 28-day mortality and prolonged ICU stay in critically ill patients with pneumonia.High glycaemic variability (GV) within 48 h of ICU admission increases 28-day mortality and prolongs ICU stay, which is consistent after adjusting for severity of illness and treatment strategy.Patients with high GV, especially those with DM or low HbA1c levels (<7.5%) should be more carefully treated to reduce mortality.

Novel Glycemic Index Based on Continuous Glucose Monitoring to Predict Poor Clinical Outcomes in Critically Ill Patients: A Pilot Study.

Aim: We explored the prospective relationship between continuous glucose monitoring (CGM) metrics and clinical outcomes in patients admitted to the intensive care unit (ICU). Materials and Methods: We enrolled critically ill patients admitted to the medical ICU. Patients with an Acute Physiology and Chronic Health Evaluation (APACHE) score ≤9 or ICU stay ≤48 h were excluded. CGM was performed for five days, and standardized CGM metrics were analyzed. The duration of ICU stay and 28-day mortality rate were evaluated as outcomes. Results: A total of 36 patients were included in this study (age [range], 49-88 years; men, 55.6%). The average APACHE score was 25.4 ± 8.3; 33 (91.7%) patients required ventilator support, and 16 (44.4%) patients had diabetes. The duration of ICU stay showed a positive correlation with the average blood glucose level, glucose management indicator (GMI), time above range, and GMI minus (-) glycated hemoglobin (HbA1c). Eight (22.2%) patients died within 28 days, and their average blood glucose levels, GMI, and GMI-HbA1c were significantly higher than those of survivors (p<0.05). After adjustments for age, sex, presence of diabetes, APACHE score, and dose of steroid administered, the GMI-HbA1c was associated with the risk of longer ICU stay (coefficient=2.34, 95% CI 0.54-4.14, p=0.017) and higher 28-day mortality rate (HR=2.42, 95% CI 1.01-5.76, p=0.046). Conclusion: The acute glycemic gap, assessed as GMI-HbA1c, is an independent risk factor for longer ICU stay and 28-day mortality rate. In the ICU setting, CGM of critically ill patients might be beneficial, irrespective of the presence of diabetes.

Nutrition influences skeletal development from childhood to adulthood: a study of hip, spine, and forearm in adolescent females.

This study evaluated the long-term efficacy of supplemental calcium and dairy products on bone mineral areal density of the hip and spine and on the bone geometry and volumetric bone mineral density of the forearm in young females during late adolescence. The study was conducted among participants of a randomized double-blinded, placebo-controlled clinical trial with calcium supplements and among participants of an observational study with higher consumption of dairy products. Hip and spine measurements by dual-energy X-ray absorptiometry were done every 6 mo (dairy group every 12 mo) during last 3 y of the follow-up while peripheral quantitative computerized tomography of the forearm was done at the last visit. The results of the study show a positive influence of calcium supplementation and dairy products on bone mineral density of the hip and the forearm. Dairy products were also associated with a higher bone mineral density of the spine while calcium supplementation did not have an effect. Calcium exerts its action on bone accretion during growth primarily by influencing volumetric bone mineral density while milk may have an additional impact on bone growth and periosteal bone expansion.