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ABSTRACT Aims/Introduction Materials and Methods Results Conclusions The study aim was to investigate sulfonylurea prescription patterns in elderly patients (age ≥65 years) with type 2 diabetes mellitus in Japan. Sulfonylurea use among older adults has been insufficiently examined, despite the associated risks of hypoglycemia.This retrospective cross‐sectional survey entailed analysis of Japanese pharmacy data, extracted from the Musubi database, for patients (age 20–100 years) prescribed sulfonylureas between November 2022 and October 2023. Dose distribution, adherence to the Diabetes Treatment Guidelines for the Elderly 2023 and coprescription of other diabetes medications were investigated.Of the total 91,229 patients, 80.1% were prescribed glimepiride, 16.3% gliclazide and 3.6% glibenclamide. In patients aged ≥65 years, exceeding the recommended dose (>1 mg/day for glimepiride, >40 mg/day for gliclazide) was numerically higher for glimepiride (25.0%) than for gliclazide (7.8%). The most common prescribing patterns were quadruple therapy with a sulfonylurea, a dipeptidyl peptidase‐4 inhibitor, an sodium–glucose transporter 2 inhibitor and a biguanide in patients aged 65 to <75 years, and dual therapy with a sulfonylurea and a dipeptidyl peptidase‐4 inhibitor in patients aged ≥75 years. Unfortunately, glinide was coprescribed for 338 (0.5%) of elderly patients. Insulin was coprescribed for 3,682 (5.6%) of elderly patients.Analysis of real‐world sulfonylurea prescription data found guideline non‐adherence, namely, excessive prescription of glimepiride, use of glibenclamide in elderly patients, and common coprescription with dipeptidyl peptidase‐4 inhibitors. These findings might provide an opportunity to reconsider the treatment of patients with type 2 diabetes mellitus who are over‐prescribed sulfonylureas to reduce residual risks, such as hypoglycemia. [ABSTRACT FROM AUTHOR]

This study aimed to compare the impact of iodosulfuron-methyl-sodium and an iodosulfuron-based herbicidal ionic liquid (HIL) on the microbiomes constituting the epiphytes and endophytes of cornflower (Centaurea cyanus L.). The experiment involved biotypes of cornflower susceptible and resistant to acetolactate synthase inhibition, examining potential bacterial involvement in sulfonylurea herbicide detoxification. We focused on microbial communities present on the surface and in the plant tissues of roots and shoots. The research included the synthesis and physicochemical analysis of a novel HIL, evaluation of shifts in bacterial community composition, analysis of the presence of catabolic genes associated with sulfonylurea herbicide degradation and determination of their abundance in all experimental variants. Overall, for the susceptible biotype, the biodiversity of the root microbiome was higher compared to shoot microbiome; however, both decreased notably after herbicide or HIL applications. The herbicide-resistant biotype showed lower degree of biodiversity changes, but shifts in community composition occurred, particularly in case of HIL treatment. [ABSTRACT FROM AUTHOR]

PURPOSE We undertook a study to investigate the relationship between duration of medication use and prevalence of impaired awareness of hypoglycemia (IAH) among patients with insulin-treated or sulfonylurea-treated type 2 diabetes in Taiwan. METHODS A total of 898 patients (41.0% insulin users, 65.1% sulfonylurea users; mean [SD] age = 59.9 [12.3] years, 50.7% female) were enrolled in pharmacies, clinics, and health bureaus of Tainan City, Taiwan. Presence of IAH was determined with Chinese versions of the Gold questionnaire (Gold-TW) and Clarke questionnaire (Clarke-TW). Sociodemographics, disease and treatment histories, diabetes-related medical care, and health status were collected. We used multiple logistic regression models to assess the relationship between duration of medication use and IAH. RESULTS Overall IAH prevalence was 41.0% (Gold-TW) and 28.2% (Clarke-TW) among insulin users, and 65.3% (Gold-TW) and 51.3% (Clarke-TW) among sulfonylurea users. Prevalence increased with the duration of sulfonylurea use, whereas it decreased with the duration of insulin use. After controlling for potential confounders, 5 or more years of sulfonylurea use was significantly associated with 3.50-fold (95% CI, 2.39-5.13) and 3.06-fold (95% CI, 2.11-4.44) increases in the odds of IAH based on the Gold-TW and Clarke-TW criteria, respectively. On the other hand, regular blood glucose testing and retinal examinations were associated with reduced odds in both insulin users and sulfonylurea users. CONCLUSIONS The prevalence of IAH was high among patients using sulfonylureas long term, but the odds of this complication were attenuated for those who received regular diabetes-related medical care. Our study suggests that long-term sulfonylurea use and irregular follow-up increase risk for IAH. Further prospective studies are needed to confirm the observed associations. [ABSTRACT FROM AUTHOR]

Background/Objective: Because of their similar appearance and inexpensive cost, sulfonylureas can cause hypoglycemia when substituted for benzodiazepines by the illicit drug market. We present a patient who developed hypoglycemia after ingestion of what she thought to be Valium; work-up revealed sulfonylurea exposure. Case Report: A 33-year-old patient was brought to the hospital after being found unresponsive by paramedics with a reported venous blood glucose level of 18 mg/dL (reference range, 70-140 mg/dL). This prompted treatment with 12.5 g of dextrose administered intravenously. At the hospital, the venous blood glucose level was 15 mg/dL resulting in intravenous dextrose infusion initiation. Once stable, the patient endorsed a medical history of substance use disorder and anxiety. She reported ingesting 2 blue pills given to her by a friend as Valium for her anxiety. Laboratory values showed an elevated insulin level of 47.4 mIU/mL (2.6-24.9), an elevated C-peptide level of 5.4 ng/mL (1.1-4.4), and a glucose level of 44 mg/dL (>70 mg/dL). The patient underwent a 72-hour fasting test. Blood hypoglycemia agent screening showed positive results for glyburide (>5 ng/mL). The patient was discharged home in stable condition. Discussion: There are approximately 2 to 5 case reports of hypoglycemia among persons taking illicit drugs containing sulfonylureas. Laboratory values consistent with the use of a hypoglycemic agent include elevated insulin and C-peptide levels, a low glucose level, and positive results for hypoglycemia agent screening. Conclusion: Sulfonylurea-induced hypoglycemia may lead to clinical sedation, mimicking the effects of benzodiazepines. Sulfonylurea substitution or drug contamination should be suspected when severe hypoglycemia is diagnosed in unresponsive patients suspected of taking illicit drugs.

Glyburide, a sulfonylurea drug used to treat type 2 diabetes, boasts neuroprotective effects by targeting the sulfonylurea receptor 1 (SUR1) and associated ion channels in various cell types, including those in the central nervous system and the retina. Previously, we demonstrated that glyburide therapy improved retinal function and structure in a rat model of diabetic retinopathy. In the present study, we explore the application of glyburide in non-neovascular ("dry") age-related macular degeneration (AMD), another progressive disease characterized by oxidative stress-induced damage and neuroinflammation that trigger cell death in the retina. We show that glyburide administration to a human cone cell line confers protection against oxidative stress, inflammasome activation, and apoptosis. To corroborate our in vitro results, we also conducted a case-control study, controlling for AMD risk factors and other diabetes medications. It showed that glyburide use in patients reduces the odds of new-onset dry AMD. A positive dose-response relationship is observed from this analysis, in which higher cumulative doses of glyburide further reduce the odds of new-onset dry AMD. In the quest for novel therapies for AMD, glyburide emerges as a promising repurposable drug given its known safety profile. The results from this study provide insights into the multifaceted actions of glyburide and its potential as a neuroprotective agent for retinal diseases; however, further preclinical and clinical studies are needed to validate its therapeutic potential in the context of degenerative retinal disorders such as AMD. [ABSTRACT FROM AUTHOR]

Background Inconsistent results have been reported regarding the association between the use of antidiabetic drugs and the clinical outcomes of coronavirus disease 2019 (COVID-19). This study aimed to investigate the effect of antidiabetic drugs on COVID-19 outcomes in patients with diabetes using data from the National Health Insurance Service (NHIS) in South Korea. Methods We analyzed the NHIS data of patients aged ≥20 years who tested positive for COVID-19 and were taking antidiabetic drugs between December 2019 and June 2020. Multiple logistic regression analysis was performed to analyze the clinical outcomes of COVID-19 based on the use of antidiabetic drugs. Results A total of 556 patients taking antidiabetic drugs tested positive for COVID-19, including 271 male (48.7%), most of whom were in their sixties. Of all patients, 433 (77.9%) were hospitalized, 119 (21.4%) received oxygen treatment, 87 (15.6%) were admitted to the intensive care unit, 31 (5.6%) required mechanical ventilation, and 61 (11.0%) died. Metformin was significantly associated with the lower risks of mechanical ventilation (odds ratio [OR], 0.281; 95% confidence interval [CI], 0.109 to 0.720; P=0.008), and death (OR, 0.395; 95% CI, 0.182 to 0.854; P=0.018). Dipeptidylpeptidase-4 inhibitor (DPP-4i) were significantly associated with the lower risks of oxygen treatment (OR, 0.565; 95% CI, 0.356 to 0.895; P=0.015) and death (OR, 0.454; 95% CI, 0.217 to 0.949; P=0.036). Sulfonylurea was significantly associated with the higher risk of mechanical ventilation (OR, 2.579; 95% CI, 1.004 to 6.626; P=0.049). Conclusion In patients with diabetes and COVID-19, metformin exhibited reduced risks of mechanical ventilation and death, DPP-4i was linked with lower risks of oxygen treatment and death, while sulfonylurea was related to the increased risk of mechanical ventilation.

Recently, a large number of studies have been conducted to investigate the variability of response in the treatment of diabetes mellitus (T2DM), which make personalized medicine possible. However, the available data are insufficient to decide on the choice of sugar-lowering drugs in T2DM. The search for phenotypic and clinical factors of pharmacogenetic response to therapy continues. Aim of the study was to investigate the relationship between the effectiveness of sulfonylurea therapy and structural variants of the ABCC8 (rs757110) and KCNJ11 (rs5219) genes in T2DM patients with clinical phenotypes. Material and methods. A cross-sectional clinical and pharmacogenetic study of 1271 patients with T2DM receiving sulfonylurea monotherapy (SU) or in combination with metformin and divided into three clinical phenotypes: with insulin deficiency (insulinopenic phenotype), with obesity and moderate insulin resistance (classical phenotype) and with severe insulin resistance (insulin-resistant phenotype) was performed. A glycated hemoglobin content of less than 7% was considered as a good response to SU therapy. Results. Patients with a good response to SU therapy with a classic phenotype had a longer duration of diabetes compared to patients with absence of good response (5.68 ± 5.22 vs 9.12 ± 6.10 years, respectively, p < 0.001) and a later age at diagnosis of T2DM (54.05 ± 7.18 vs 49.37 ± 7.65 years, respectively, p < 0.001); patients with an insulin-resistant phenotype had T2DM established at an older age (54.35 ± 7.91 vs 50.10 ± 7.51 years, respectively, p = 0.001). Logistic regression analysis did not reveal a statistically significant association of the genotype of the structural variant of the ABCC8 gene (rs757110) with the effectiveness of SU in clinical phenotypes. The T/T genotype of the KCNJ11 gene (rs5219) was associated with a better response to SU therapy only in the group of T2DM patients with the classic phenotype (odds ratio 1.85, 95% confidence interval 1.05–3.25, p = 0.041). Conclusions. In patients with type 2 diabetes, predictors of a good response to SU with a classic phenotype were a later age of T2DM diagnosis, a shorter duration of diabetes, and the presence of the T/T genotype of the structural variant of the KCNJ11 gene (rs5219); with an insulin-resistant phenotype, a later age of T2DM diagnosis; with the insulinopenic phenotype no clinical and genetic predictors of the SU effectiveness were identified.

Purpose: The prevalent new user design extends the active comparator new user design to include patients switching to a treatment of interest from a comparator. We examined the impact of adding "switchers" to incident new users on the estimated hazard ratio (HR) of hospitalized heart failure. Methods: Using MarketScan claims data (2000–2014), we estimated HRs of hospitalized heart failure between patients initiating GLP‐1 receptor agonists (GLP‐1 RA) and sulfonylureas (SU). We considered three estimands: (1) the effect of incident new use; (2) the effect of switching; and (3) the effect of incident new use or switching, combining the two population. We used time‐conditional propensity scores (TCPS) and time‐stratified standardized morbidity ratio (SMR) weighting to adjust for confounding. Results: We identified 76 179 GLP‐1 RA new users, of which 12% were direct switchers (within 30 days) from SU. Among incident new users, GLP‐1 RA was protective against heart failure (adjHRSMR = 0.74 [0.69, 0.80]). Among switchers, GLP‐1 RA was not protective (adjHRSMR = 0.99 [0.83, 1.18]). Results in the combined population were largely driven by the incident new users, with GLP‐1 RA having a protective effect (adjHRSMR = 0.77 [0.72, 0.83]). Results using TCPS were consistent with those estimated using SMR weighting. Conclusions: When analyses were conducted only among incident new users, GLP‐1 RA had a protective effect. However, among switchers from SU to GLP‐1 RA, the effect estimates substantially shifted toward the null. Combining patients with varying treatment histories can result in poor confounding control and camouflage important heterogeneity. [ABSTRACT FROM AUTHOR]

Super bacterial infection caused by metallo‐β‐lactamases (MβLs) has posed a serious public health threat, while developing inhibitors of MβLs is an ideal strategy to combat drug‐resistance. Here, seventeen sulfonylureas were synthesized and confirmed. Biological assay shown that these molecules effectively inhibited MβL ImiS, with an IC50 value in the range of 29.5–188.2 μM, and the best inhibitor competitively and irreversibly inhibited ImiS with a Ki value of 15.2 μM. Structure‐activity relationship analysis revealed that the chlorine‐substituted phenyl significantly raised inhibitory activity of sulfonylureas on ImiS. Antibacterial and chessboard dilution assays shown that the most sulfonylureas tested enhanced antimicrobial effect of meropenem (MER) on E. coli‐ImiS, and the two inhibitors with best effect resulted in an 8‐fold reduction in MIC of MER. Mice tests shown that the best inhibitor synergizing MER virtually diminished the load of E. coli‐ImiS in spleen and liver. Docking study revealed that the sulfonylurea reacts with ImiS mainly through the sulfonyl group, in which one of oxygen atoms coordinates to Zn(II), and forms two hydrogen bonds with Lys224 (2.1 Å) and His263 (3.1 Å). This work revealed the sulfonylureas are promising candidates for the development of ImiS inhibitors. [ABSTRACT FROM AUTHOR]

Introduction: Hyperinsulinemia and hyperglycemia are associated with exaggerated systemic sympathetic nerve activity (SNA) in patients with type 2 diabetes. Sodium–glucose cotransporter 2 (SGLT2) inhibitors lower insulin levels, whereas sulfonylureas increase insulin levels. We will test whether these two classes of antidiabetic agents have different effects on SNA. Methods: The present study is an ongoing, 24-week, one-center (only Kanazawa University Hospital), open-label, randomized, parallel trial (jRCTs 041200035). Participants with type 2 diabetes with multiple atherosclerosis risk factors are randomly assigned in a 1:1 manner to receive 2.5 mg luseogliflozin or 0.5 mg glimepiride once daily. The sample size was calculated to be 14 in each group, with a significance level of 0.05 and a power of 0.80. The design required 40 evaluable study participants. Our primary endpoint will be the change in muscle SNA (MSNA). The secondary endpoints included organ-specific insulin sensitivity measured by a hyperinsulinemic-euglycemic clamp study using an artificial pancreas combined with a stable isotope-labeled glucose infusion, bioelectrical impedance analysis, and organ-specific (cardiac, renal, and hepatic) 123I-meta-iodobenzylguanidine (MIBG) innervation imaging. Planned Outcomes: Study recruitment started in April 2020 and will end in June 2024, with 40 participants randomized into the two groups. The treatment follow-up of the participants is currently ongoing and is due to finish by March 2025. Trial Registration: The study protocol has been approved by the Certified Review Board, Kanazawa University, Ishikawa, Japan, in accordance with the guidelines stipulated in the Declaration of Helsinki (CRB4180005, 2019-001). This trial is registered with the Japan Registry of Clinical Trials, jRCTs 041200035. [ABSTRACT FROM AUTHOR]

Abstract The incretin hormones glucagon‐like peptide‐1 (GLP‐1) and glucose‐dependent insulinotropic polypeptide (GIP), are thought to be the main drivers of insulin secretion in individuals with sulfonylurea (SU)‐treated KCNJ11 permanent neonatal diabetes. The aim of this study was to assess for the first time the incretin hormone response to carbohydrate and protein/fat in adults with sulfonylurea‐treated KCNJ11 permanent neonatal diabetes compared with that of controls without diabetes. Participants were given a breakfast high in carbohydrate and an isocaloric breakfast high in protein/fat on two different mornings. Incremental area under the curve and total area under the curve (0‐240 minutes) for total GLP‐1 and GIP were compared between groups, using non‐parametric statistical methods. Post‐meal GLP‐1 and GIP secretion were similar in cases and controls, suggesting this process is adenosine triphosphate‐sensitive potassium channel‐independent. Future research will investigate whether treatments targeting the incretin pathway are effective in individuals with KCNJ11 permanent neonatal diabetes who do not have good glycemic control on sulfonylurea alone.

BackgroundOral hypoglycemic agents are a frequent cause of hypoglycemia in nondiabetic people. Here, we report a case of recurrent hypoglycemia caused by glipizide, in which diagnosis was delayed because of a combination of delayed hypoglycemic agent screening and low sensitivity of the hypoglycemic agent screening panel used.Case reportA 66-year-old woman repeatedly presented with symptomatic hypoglycemia. At the first presentation, the serum glucose level was 40 mg/dL (2.2 mmol/L), C-peptide level was 13.1 ng/mL (0.8-3.1 ng/mL), proinsulin level was 96.9 pmol/L (

The incretin hormones glucagon‐like peptide‐1 (GLP‐1) and glucose‐dependent insulinotropic polypeptide (GIP), are thought to be the main drivers of insulin secretion in individuals with sulfonylurea (SU)‐treated KCNJ11 permanent neonatal diabetes. The aim of this study was to assess for the first time the incretin hormone response to carbohydrate and protein/fat in adults with sulfonylurea‐treated KCNJ11 permanent neonatal diabetes compared with that of controls without diabetes. Participants were given a breakfast high in carbohydrate and an isocaloric breakfast high in protein/fat on two different mornings. Incremental area under the curve and total area under the curve (0‐240 minutes) for total GLP‐1 and GIP were compared between groups, using non‐parametric statistical methods. Post‐meal GLP‐1 and GIP secretion were similar in cases and controls, suggesting this process is adenosine triphosphate‐sensitive potassium channel‐independent. Future research will investigate whether treatments targeting the incretin pathway are effective in individuals with KCNJ11 permanent neonatal diabetes who do not have good glycemic control on sulfonylurea alone. [ABSTRACT FROM AUTHOR]

Aims/hypothesis: Correctly diagnosing MODY is important, as individuals with this diagnosis can discontinue insulin injections; however, many people are misdiagnosed. We aimed to develop a robust approach for determining the pathogenicity of variants of uncertain significance in hepatocyte nuclear factor-1 alpha (HNF1A)-MODY and to obtain an accurate estimate of the prevalence of HNF1A-MODY in paediatric cases of diabetes. Methods: We extended our previous screening of the Norwegian Childhood Diabetes Registry by 830 additional samples and comprehensively genotyped HNF1A variants in autoantibody-negative participants using next-generation sequencing. Carriers of pathogenic variants were treated by local healthcare providers, and participants with novel likely pathogenic variants and variants of uncertain significance were enrolled in an investigator-initiated, non-randomised, open-label pilot study (ClinicalTrials.gov registration no. NCT04239586). To identify variants associated with HNF1A-MODY, we functionally characterised their pathogenicity and assessed the carriers' phenotype and treatment response to sulfonylurea. Results: In total, 615 autoantibody-negative participants among 4712 cases of paediatric diabetes underwent genetic sequencing, revealing 19 with HNF1A variants. We identified nine carriers with novel variants classified as variants of uncertain significance or likely to be pathogenic, while the remaining ten participants carried five pathogenic variants previously reported. Of the nine carriers with novel variants, six responded favourably to sulfonylurea. Functional investigations revealed their variants to be dysfunctional and demonstrated a correlation with the resulting phenotype, providing evidence for reclassifying these variants as pathogenic. Conclusions/interpretation: Based on this robust classification, we estimate that the prevalence of HNF1A-MODY is 0.3% in paediatric diabetes. Clinical phenotyping is challenging and functional investigations provide a strong complementary line of evidence. We demonstrate here that combining clinical phenotyping with functional protein studies provides a powerful tool to obtain a precise diagnosis of HNF1A-MODY. [ABSTRACT FROM AUTHOR]

In this study, some new sulfonylurea derivatives based on the sulfanilamide compound were synthesized. IR, 1H-NMR, 13C-NMR spectroscopic methods and elemental analysis data were used to confirm the structures of the synthesized compounds. ABTS, DPPH, Cuprac and β-Carotene/linoleic acid assays were performed to evaluate the antioxidant activities of sulphonylurea derivatives. The activities of these compounds against some enzymes (acetylcholinesterase, butrylcholinesterase, tyrosinase, α-amylase and α-glucosidase) were also investigated. Compounds S7, S8, S13 and S14 showed inhibitory activity against α-amylase enzyme with IC50 values of 227.84±1.48- 298.27±8.61 µM. In addition, the drug-likeness properties and solubility of the compounds were determined by computational programs. [ABSTRACT FROM AUTHOR]

Real-world evidence (RWE) plays an important role in the management of type 2 diabetes (T2D). It provides data about the effectiveness and safety of an intervention from outside the randomised controlled trial (RCT) setting and allows healthcare professionals (HCPs) to determine if RCT data are applicable to their patients in routine clinical practice. This review provides a discussion of the value of RWE in T2D management in day-to-day clinical practice, with a focus on RWE with sulfonylureas (SUs), and presents two examples of a new generation of international real-world studies in people with T2D managed in routine clinical practice. RWE plays a valuable role in advising HCPs in the day-to-day management of T2D, informing regulatory authorities with regard to pharmacovigilance and post-approval updates, and providing insights with regard to patients' treatment adherence and preference. RWE should be used alongside RCTs to increase HCP awareness and understanding of their patients' perspectives, potentially allowing for improvements in treatment adherence, glycaemic control and health-related quality of life (HRQoL). In addition, real-world studies must be conducted in a way that generates robust RWE by limiting the risks of bias and confounding as much as possible. A growing body of RWE is emerging from Asia. For example, in a preliminary HRQoL analysis of the Joint Asia Diabetes Evaluation (JADE) Register, Asian people with T2D had better HRQoL with gliclazide-based treatment than with other SU agents, despite being older and having more diabetes-related complications. [ABSTRACT FROM AUTHOR]

Herein, we describe the design, synthesis and biological evaluation of a series of novel non-nucleotide sulfonylurea and sulfonylthiourea based small molecule inhibitors of h-ENPP1, h-ENPP3 and e5′NT. Among the tested compounds, 3b inhibited h-ENPP1 with an IC50 value of 0.11 ± 0.01 µM. Similarly, 4b was found to be the most potent inhibitor tested against h-ENPP3 with an IC50 value of 0.038 ± 0.02 µM. Compound 3a revealed remarkable inhibitory potency against human ecto-5′-nucleotidase with an IC50 value of 0.83 ± 0.01 µM while compound 3b possessed IC50 value of 0.26 ± 0.05 µM against rat ecto-5′-nucleotidase. Antiproliferative activity of novel sulfonylurea and sulfonylthiourea derivatives was investigated on breast cancer cell line (MCF-7). Compound 4a showed anticancer activity against MCF-7 cell line with percentage inhibition of 64 and successfully arrested the viability of cancer cells. The compounds were not cytotoxic to the normal cells derived from baby hamster kidney (BHK-21).

Abstract Background Previous studies have assessed the association between antidiabetic drugs and stroke risk, but the results are inconsistent. Mendelian randomization (MR) was used to assess effects of antidiabetic drugs on stroke risk. Methods We selected blood glucose-lowering variants in genes encoding antidiabetic drugs targets from genome-wide association studies (GWAS). A two-sample MR and Colocalization analyses were applied to examine associations between antidiabetic drugs and the risk of stroke. For antidiabetic agents that had effect on stroke risk, an independent blood glucose GWAS summary data was used for further verification. Results Genetic proxies for sulfonylureas targets were associated with reduced risk of any stroke (OR=0.062, 95% CI 0.013-0.295, P=4.65×10－4) and any ischemic stroke (OR=0.055, 95% CI 0.010-0.289, P=6.25×10－4), but not with intracranial hemorrhage. Colocalization supported shared casual variants for blood glucose with any stroke and any ischemic stroke within the encoding genes for sulfonylureas targets (KCNJ11 and ABCC8) (posterior probability>0.7). Furthermore, genetic variants in the targets of insulin/insulin analogues, glucagon-like peptide-1 analogues, thiazolidinediones, and metformin were not associated with the risk of any stroke, any ischemic stroke and intracranial hemorrhage. The association was consistent in the analysis of sulfonylureas with stroke risk using an independent blood glucose GWAS summary data. Conclusions Our findings showed that genetic proxies for sulfonylureas targets by lowering blood glucose were associated with a lower risk of any stroke and any ischemic stroke. The study might be of great significance to guide the selection of glucose-lowering drugs in individuals at high risk of stroke.

Abstract Background Hip fracture is a major health problem that occurs more often in the elderly, especially in diabetic patients. Some studies have been conducted regarding the effect of anti- diabetic drugs on fractures. But so far, no meta-analysis study has been conducted to investigate the effect of diabetic drugs on hip fractures. Therefore, this study investigated the relationship between anti-diabetic drugs (Metformin, Sulfonylurea, and insulin) with hip fractures. Methods In this systematic review and meta analysis study, PubMed, Scopus, Google Scholar, and Web of Science databases were searched with specific keywords to find relevant studies. Two researchers included related studies after screening based on the title and full text. Cochran’s Q and I2 tests were used to assess heterogeneity between studies. Publication bias between studies was evaluated for each drug using Egger’s test. A 95% confidence interval was used for effect size significance. Overall, 49 studies, including 6,631,297 participants, were reviewed. Results The results showed that metformin significantly reduced the risk of hip fracture (HR: 0.833, 95% CI: 0.759, 0.914, P:0.001). Consumption of sulfonylurea compounds was significantly associated with an increased risk of hip fracture. (HR: 1.175, 95% CI:1.068,1.293, P:0.001), The risk of hip fracture in patients receiving insulin was significantly higher than in diabetic patients who did not receive insulin. (HR:1.366, 95% CI:1.226,1.522, P:0.001). Conclusion The results of this study showed that taking metformin reduces the risk of hip fracture, and insulin and Sulfonylurea increase the risk of hip fracture.

Abstract Background Biguanides and sulfonylurea are two classes of anti-diabetic medications that have commonly been prescribed all around the world. Diagnosis of biguanide and sulfonylurea exposures is based on history taking and physical examination; thus, physicians might misdiagnose these two different clinical settings. We aimed to conduct a study to develop a model based on decision tree analysis to help physicians better diagnose these poisoning cases. Methods The National Poison Data System was used for this six-year retrospective cohort study.The decision tree model, common machine learning models multi layers perceptron, stochastic gradient descent (SGD), Adaboosting classiefier, linear support vector machine and ensembling methods including bagging, voting and stacking methods were used. The confusion matrix, precision, recall, specificity, f1-score, and accuracy were reported to evaluate the model’s performance. Results Of 6183 participants, 3336 patients (54.0%) were identified as biguanides exposures, and the remaining were those with sulfonylureas exposures. The decision tree model showed that the most important clinical findings defining biguanide and sulfonylurea exposures were hypoglycemia, abdominal pain, acidosis, diaphoresis, tremor, vomiting, diarrhea, age, and reasons for exposure. The specificity, precision, recall, f1-score, and accuracy of all models were greater than 86%, 89%, 88%, and 88%, respectively. The lowest values belong to SGD model. The decision tree model has a sensitivity (recall) of 93.3%, specificity of 92.8%, precision of 93.4%, f1_score of 93.3%, and accuracy of 93.3%. Conclusion Our results indicated that machine learning methods including decision tree and ensembling methods provide a precise prediction model to diagnose biguanides and sulfonylureas exposure.

Background: Previous studies have assessed the association between antidiabetic drugs and stroke risk, but the results are inconsistent. Mendelian randomization (MR) was used to assess effects of antidiabetic drugs on stroke risk. Methods: We selected blood glucose-lowering variants in genes encoding antidiabetic drugs targets from genome-wide association studies (GWAS). A two-sample MR and Colocalization analyses were applied to examine associations between antidiabetic drugs and the risk of stroke. For antidiabetic agents that had effect on stroke risk, an independent blood glucose GWAS summary data was used for further verification. Results: Genetic proxies for sulfonylureas targets were associated with reduced risk of any stroke (OR=0.062, 95% CI 0.013-0.295, P=4.65×10－4) and any ischemic stroke (OR=0.055, 95% CI 0.010-0.289, P=6.25×10－4), but not with intracranial hemorrhage. Colocalization supported shared casual variants for blood glucose with any stroke and any ischemic stroke within the encoding genes for sulfonylureas targets (KCNJ11 and ABCC8) (posterior probability>0.7). Furthermore, genetic variants in the targets of insulin/insulin analogues, glucagon-like peptide-1 analogues, thiazolidinediones, and metformin were not associated with the risk of any stroke, any ischemic stroke and intracranial hemorrhage. The association was consistent in the analysis of sulfonylureas with stroke risk using an independent blood glucose GWAS summary data. Conclusions: Our findings showed that genetic proxies for sulfonylureas targets by lowering blood glucose were associated with a lower risk of any stroke and any ischemic stroke. The study might be of great significance to guide the selection of glucose-lowering drugs in individuals at high risk of stroke. [ABSTRACT FROM AUTHOR]

Context: The design and synthesis of safe and highly active sulfonylurea herbicides is still a challenge. Therefore, following some principles of structure-activity relationship (SAR) of sulfonylurea herbicides, this work focuses on evaluating two sulfonylurea derivatives bearing electron-withdrawing substituents, namely, –(CO)OCH3 and –NO2 on the aryl group, on herbicidal activity. To understand the effects caused by the substituent groups, the molecular and electronic structures of the sulfonylureas were evaluated by density functional theory. Likewise, the crystalline supramolecular arrangements of both compounds were analyzed by Hirshfeld surface, QTAIM, and NBO, with the aim of verifying changes in intermolecular interactions caused by substituent groups. Finally, through a toxicophoric analysis, we were able to predict the interacting groups in their biological target, acetolactate synthase, and verify the interactions with the binding site. Methods: All theoretical calculations were conducted using the highly parameterized empirical exchange-correlation functional M06-2X accompanied by the diffuse and polarized basis set 6-311++G(d,p). The atomic coordinates were obtained directly from the crystalline structures, and from the energies of the frontier molecular orbitals (HOMO and LUMO), chemical descriptors were obtained that indicated the influence of the functional groups in the sulfonylureas on the reactivity of the molecules. The intermolecular interactions in the crystals were analyzed using the Hirshfeld, QTAIM, and NBO surfaces. Toxicophoric modeling was performed by the PharmaGist webserver and molecular docking calculations were performed by the GOLD 2022.1.0 software package so that the ligand was fitted to the binding site in a 10 Å sphere. For this, genetic algorithm parameters were used using the ChemPLP scoring function for docking and ASP for redocking. [ABSTRACT FROM AUTHOR]

Aims/hypothesis: Characterisation of genetic variation that influences the response to glucose-lowering medications is instrumental to precision medicine for treatment of type 2 diabetes. The Study to Understand the Genetics of the Acute Response to Metformin and Glipizide in Humans (SUGAR-MGH) examined the acute response to metformin and glipizide in order to identify new pharmacogenetic associations for the response to common glucose-lowering medications in individuals at risk of type 2 diabetes. Methods: One thousand participants at risk for type 2 diabetes from diverse ancestries underwent sequential glipizide and metformin challenges. A genome-wide association study was performed using the Illumina Multi-Ethnic Genotyping Array. Imputation was performed with the TOPMed reference panel. Multiple linear regression using an additive model tested for association between genetic variants and primary endpoints of drug response. In a more focused analysis, we evaluated the influence of 804 unique type 2 diabetes- and glycaemic trait-associated variants on SUGAR-MGH outcomes and performed colocalisation analyses to identify shared genetic signals. Results: Five genome-wide significant variants were associated with metformin or glipizide response. The strongest association was between an African ancestry-specific variant (minor allele frequency [MAFAfr]=0.0283) at rs149403252 and lower fasting glucose at Visit 2 following metformin (p=1.9×10−9); carriers were found to have a 0.94 mmol/l larger decrease in fasting glucose. rs111770298, another African ancestry-specific variant (MAFAfr=0.0536), was associated with a reduced response to metformin (p=2.4×10−8), where carriers had a 0.29 mmol/l increase in fasting glucose compared with non-carriers, who experienced a 0.15 mmol/l decrease. This finding was validated in the Diabetes Prevention Program, where rs111770298 was associated with a worse glycaemic response to metformin: heterozygous carriers had an increase in HbA1c of 0.08% and non-carriers had an HbA1c increase of 0.01% after 1 year of treatment (p=3.3×10−3). We also identified associations between type 2 diabetes-associated variants and glycaemic response, including the type 2 diabetes-protective C allele of rs703972 near ZMIZ1 and increased levels of active glucagon-like peptide 1 (GLP-1) (p=1.6×10−5), supporting the role of alterations in incretin levels in type 2 diabetes pathophysiology. Conclusions/interpretation: We present a well-phenotyped, densely genotyped, multi-ancestry resource to study gene–drug interactions, uncover novel variation associated with response to common glucose-lowering medications and provide insight into mechanisms of action of type 2 diabetes-related variation. Data availability: The complete summary statistics from this study are available at the Common Metabolic Diseases Knowledge Portal (https://hugeamp.org) and the GWAS Catalog (www.ebi.ac.uk/gwas/, accession IDs: GCST90269867 to GCST90269899). [ABSTRACT FROM AUTHOR]

IntroductionVERTIS CV is the cardiovascular outcome trial for the sodium-glucose cotransporter 2 (SGLT2) inhibitor ertugliflozin. A sub-study was conducted to assess the efficacy and safety of ertugliflozin in patients with type 2 diabetes mellitus (T2DM) inadequately glycemic-controlled on metformin and a sulfonylurea (SU).MethodsPatients with T2DM, established atherosclerotic cardiovascular disease (ASCVD), and an HbA1c of 7.0-10.5% on stable metformin (≥ 1500 mg/day) and moderate to high SU doses were randomly assigned to once-daily ertugliflozin (5 or 15 mg) or placebo. The primary sub-study objectives were to assess the effect of ertugliflozin on HbA1c compared with placebo and to evaluate safety following 18 weeks of treatment. Key secondary endpoints included changes in fasting plasma glucose (FPG), body weight (BW), blood pressure (BP), and the proportion of patients achieving HbA1c

Chronic pain is a substantial health burden and options for treating chronic pain remain minimally effective. Ketogenic diets are emerging as well-tolerated, effective therapeutic strategies in preclinical models of chronic pain, especially diabetic neuropathy. We tested whether a ketogenic diet is antinociceptive through ketone oxidation and related activation of ATP-gated potassium (KATP) channels in mice. We demonstrate that consumption of a ketogenic diet for one week reduced evoked nocifensive behaviors (licking, biting, lifting) following intraplantar injection of different noxious stimuli (methylglyoxal, cinnamaldehyde, capsaicin, or Yoda1) in mice. A ketogenic diet also decreased the expression of p-ERK, an indicator of neuronal activation in the spinal cord, following peripheral administration of these stimuli. Using a genetic mouse model with deficient ketone oxidation in peripheral sensory neurons, we demonstrate that protection against methylglyoxal-induced nociception by a ketogenic diet partially depends on ketone oxidation by peripheral neurons. Injection of tolbutamide, a KATP channel antagonist, prevented ketogenic diet-mediated antinociception following intraplantar capsaicin injection. Tolbutamide also restored the expression of spinal activation markers in ketogenic diet-fed, capsaicin-injected mice. Moreover, activation of KATP channels with the KATP channel agonist diazoxide reduced pain-like behaviors in capsaicin-injected, chow-fed mice, similar to the effects observed with a ketogenic diet. Diazoxide also reduced the number of p-ERK+ cells in capsaicin-injected mice. These data support a mechanism that includes neuronal ketone oxidation and activation of KATP channels to provide ketogenic diet-related analgesia. This study also identifies KATP channels as a new target to mimic the antinociceptive effects of a ketogenic diet.

Background: Diabetes mellitus (DM) is associated with high blood glucose levels and sulfonylureas (SFUs) are one of the treatment options for DM. SFUs bind to sulfonylurea-1 receptor (SUR1), which is encoded by the ABCC8 gene and leads to blood glucose reduction. Genetic variants like rs757110 and rs1799854 of ABCC8 can influence the response to the drug's efficiency. Therefore, this study aimed to investigate the association between the ABCC8 rs757110 and rs1799854 genetic variants and response to SFUs treatment. Methods: Totally, 61 DM patients with SFUs treatment were included. Baseline characteristics of the patients were recorded and 5 ml of blood was taken from each patient. After DNA extraction, a sequence containing rs757110 and rs1799854 was synthesized by the PCR method, and the PCR products were used for Sanger sequencing. Results: Frequencies of GG, GA, and AA genotypes of rs1799854 variant was 12 (40%), 14 (46.7%), and 4 (13.3%), and the frequencies of CC, AC, and AA genotypes for rs757110 variant was 3 (9.7%), 5 (16.1%) and 23 (74.2%) in, respectively. Patients with different genotypes had the same age, BMI (body mass index), initial FBS (Fasting blood sugar), initial HbA1c, treatment duration, gender and history of smoking, alcohol consumption, and exercise. There was no significant difference in FBS and HbA1c changes after SFUs treatment between patients with rs757110 variant (p = 0.39 for FBS and p = 0.76 for HbA1c) and rs1799854 (p = 0.24 for FBS and p = 0.36 for HbA1c). Conclusion: The rs1799854 and rs757110 variants of the ABCC8 gene had no significant influence on response to SFUs treatment. [ABSTRACT FROM AUTHOR]

Background: Hip fracture is a major health problem that occurs more often in the elderly, especially in diabetic patients. Some studies have been conducted regarding the effect of anti- diabetic drugs on fractures. But so far, no meta-analysis study has been conducted to investigate the effect of diabetic drugs on hip fractures. Therefore, this study investigated the relationship between anti-diabetic drugs (Metformin, Sulfonylurea, and insulin) with hip fractures. Methods: In this systematic review and meta analysis study, PubMed, Scopus, Google Scholar, and Web of Science databases were searched with specific keywords to find relevant studies. Two researchers included related studies after screening based on the title and full text. Cochran's Q and I2 tests were used to assess heterogeneity between studies. Publication bias between studies was evaluated for each drug using Egger's test. A 95% confidence interval was used for effect size significance. Overall, 49 studies, including 6,631,297 participants, were reviewed. Results: The results showed that metformin significantly reduced the risk of hip fracture (HR: 0.833, 95% CI: 0.759, 0.914, P:0.001). Consumption of sulfonylurea compounds was significantly associated with an increased risk of hip fracture. (HR: 1.175, 95% CI:1.068,1.293, P:0.001), The risk of hip fracture in patients receiving insulin was significantly higher than in diabetic patients who did not receive insulin. (HR:1.366, 95% CI:1.226,1.522, P:0.001). Conclusion: The results of this study showed that taking metformin reduces the risk of hip fracture, and insulin and Sulfonylurea increase the risk of hip fracture. [ABSTRACT FROM AUTHOR]

Background: Biguanides and sulfonylurea are two classes of anti-diabetic medications that have commonly been prescribed all around the world. Diagnosis of biguanide and sulfonylurea exposures is based on history taking and physical examination; thus, physicians might misdiagnose these two different clinical settings. We aimed to conduct a study to develop a model based on decision tree analysis to help physicians better diagnose these poisoning cases. Methods: The National Poison Data System was used for this six-year retrospective cohort study.The decision tree model, common machine learning models multi layers perceptron, stochastic gradient descent (SGD), Adaboosting classiefier, linear support vector machine and ensembling methods including bagging, voting and stacking methods were used. The confusion matrix, precision, recall, specificity, f1-score, and accuracy were reported to evaluate the model's performance. Results: Of 6183 participants, 3336 patients (54.0%) were identified as biguanides exposures, and the remaining were those with sulfonylureas exposures. The decision tree model showed that the most important clinical findings defining biguanide and sulfonylurea exposures were hypoglycemia, abdominal pain, acidosis, diaphoresis, tremor, vomiting, diarrhea, age, and reasons for exposure. The specificity, precision, recall, f1-score, and accuracy of all models were greater than 86%, 89%, 88%, and 88%, respectively. The lowest values belong to SGD model. The decision tree model has a sensitivity (recall) of 93.3%, specificity of 92.8%, precision of 93.4%, f1_score of 93.3%, and accuracy of 93.3%. Conclusion: Our results indicated that machine learning methods including decision tree and ensembling methods provide a precise prediction model to diagnose biguanides and sulfonylureas exposure. [ABSTRACT FROM AUTHOR]

ABSTRACT Aims/Introduction Aging of society is accelerating in many countries. The purpose of this study was to describe the clinical features and sulfonylurea usage among diabetes outpatients aged ≥90 years (nonagenarians). Materials and Methods This study was a retrospective observational study. The study population consisted of 69 nonagenarian diabetes outpatients and 857 diabetes outpatients aged

Abstract Background Safety of sulfonylurea drugs in the treatment of Type 2 Diabetes is still under debate. The aim of this study was to compare the all-cause mortality and cardiovascular adverse events of sulfonylureas and drugs with a low risk for hypoglycaemia in adults with type 2 diabetes. Methods Systematic review and meta-analysis of randomised controlled trials. Data sources: MEDLINE (PubMed, OVID), Embase, Cochrane Central Register of Controlled Trials, CINAHL, WOS and Lilacs. Study selection Randomised controlled head-to-head trials that compared sulfonylureas with active control with low hypoglycaemic potential in adults (≥ 18 years old) with type 2 diabetes published up to August 2015. The drug classes involved in the analysis were metformin, dipeptidyl peptidase-4 (DPP-4) inhibitors, sodium-glucose co-transporter-2 (SGLT-2) inhibitors and glucagon-like peptide-1 (GLP-1) receptor agonists. Outcomes The primary endpoint was all-cause mortality. The secondary endpoints were MACE, cardiovascular events and severe hypoglycaemia. Synthesis of results: Two reviewers checked study eligibility, independently extracted data and assessed quality with disagreements resolved through discussion. We assessed the risk of bias of the included studies using the Cochrane risk of bias tool for randomized trials v2. Pooled odds ratios (ORs) were estimated by using fixed effects model. The study is registered on PROSPERO (26/05/2016 CRD42016038780). Results Our final analysis comprised 31 studies (26,204 patients, 11,711 patients given sulfonylureas and 14,493 given comparator drugs). In comparison to drugs with low hypoglycaemic potential, sulfonylureas had higher odds for all-cause mortality (OR 1.32, 95% CI 1.00-1.75), MACE (OR 1.32, 95% CI 1.07–1.61), myocardial infarction (fatal and non-fatal) (OR 1.67, 95% CI 1.17–2.38) and hypoglycaemia (OR 5.24, 95% CI 4.20–6.55). Subsequent sensitivity analysis revealed differences in the effect of sulfonylureas, with an increased risk of all-cause mortality with glipizide but not the other molecules. Conclusion Our meta-analysis raises concern about the safety of SUs compared to alternative drugs involved in current analysis. Important differences may exist within the drug class, and glimepiride seems to have best safety profile.

A 24-year-old man with diabetes mellitus presented with advanced kidney disease and severe proteinuria. Genetic testing revealed ABCC8-MODY12 (OMIM 600509), and a kidney biopsy showed nodular glomerulosclerosis. He commenced dialysis shortly thereafter, and glycemic control improved on treatment with a sulfonylurea. Diabetic end-stage kidney disease in patients with ABCC8-MODY12 has not been reported until now. Thus, our case highlights the risk for early-onset and severe diabetic kidney disease in patients with ABCC8-MODY12 and the importance of timely genetic diagnosis in unusual cases of diabetes to allow for proper treatment and prevention of late sequelae of diabetes. [ABSTRACT FROM AUTHOR]

Copyright of Chinese Journal of Oil Crop Sciences is the property of Oil Crops Research Institute of Chinese Academy of Agricultural Sciences and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

The International Society of Pediatric and Adolescent Diabetes (ISPAD) recommends metformin (MET) use for metabolic disturbances and hyperglycemia, either in combination with insulin therapy or alone. A caveat of MET therapy has been suggested to be biochemical vitamin B12 deficiency, as seen mainly in studies conducted in adults. In the present case–control study, children and adolescents of different weight status tiers on MET therapy for a median of 17 months formed the cases group (n = 23) and were compared with their peers not taking MET (n = 46). Anthropometry, dietary intake, and blood assays were recorded for both groups. MET group members were older, heavier, and taller compared with the controls, although BMI z-scores did not differ. In parallel, blood phosphorus and alkaline phosphatase (ALP) concentrations were lower in the MET group, whereas MCV, Δ4-androstenedione, and DHEA-S were higher. No differences were observed in the HOMA-IR, SHBG, hemoglobin, HbA1c, vitamin B12, or serum 25(OH)D3 concentrations between groups. Among those on MET, 17.4% exhibited vitamin B12 deficiency, whereas none of the controls had low vitamin B12 concentrations. Participants on MET therapy consumed less energy concerning their requirements, less vitamin B12, more carbohydrates (as a percentage of the energy intake), and fewer fats (including saturated and trans fats) compared with their peers not on MET. None of the children received oral nutrient supplements with vitamin B12. The results suggest that, in children and adolescents on MET therapy, the dietary intake of vitamin B12 is suboptimal, with the median coverage reaching 54% of the age- and sex-specific recommended daily allowance. This low dietary intake, paired with MET, may act synergistically in reducing the circulating vitamin B12 concentrations. Thus, caution is required when prescribing MET in children and adolescents, and replacement is warranted. [ABSTRACT FROM AUTHOR]

A Gram-stain-negative, motile, rod-shaped bacterium, designated strain LAM2020T, was isolated from a sulfonylurea herbicides-degrading bacterial consortium. The optimal temperature and pH for the growth of strain LAM2020T were 30 °C and 7.0, respectively. Strain LAM2020T formed a distinct phylogenetic subclade within the genus Cedecea in the phylogenetic trees built with 16S rRNA gene sequences and shared the highest similarity with Cedecea davisae DSM 4568T (98.4%). The values of digital DNA–DNA hybridization and average nucleotide identity (ANI) based on the genome sequences between LAM2020T and C. davisae DSM 4568T were 22.7% and 80.0%, respectively. It contained 54.0 mol% of G + C in the genomic DNA. The major cellular fatty acids of strain LAM2020T were summed feature 3 (C16:1ω6c and/or C16:1ω7c), C16:0 and summed feature 8 (C18:1ω7c/C18:1ω6c). The major polar lipids present in strain LAM2020T were diphosphatidylglycerol, phosphatidylglycerol, phosphatidylethanolamine and aminophospholipid. The respiratory quinone of strain LAM2020T was ubiquinone-8 and ubiquinone-7. Based on the phenotypic characteristics, chemotaxonomic data and genotypic analyses, strain LAM2020T should be classified as a novel species of genus Cedecea, for which the name Cedecea sulfonylureivorans sp. nov. is proposed. The type strain is LAM2020T (= GDMCC 1.2363T = JCM 34640T). [ABSTRACT FROM AUTHOR]

The migration of residual amounts of sulfonylurea and imidazolinone herbicides under conditions of washing water regime (sum of precipitation in forest and forest-steppe natural zone within 400-600 mm) in practice of intensive agricultural production has been studied. Vertical moisture transport in the soil determines the number of large pores, voids and cracks, and herbicide mobility depends on solubility of the active substance in water and adsorption equilibrium between the soil solution and the soil solid phase. The herbicide was applied to the soil surface, as is the case in practice. Then, pure water (without herbicide) was fed into the column from above, and the movement of water along the soil profile, as well as the adsorption of the herbicide by the soil and the desorption of the active substance by water, were simulated. The water supply to the column was stopped when the portions of water collected after filtering the water through the column contained less than the detection limit of herbicide residues chromatographically. The percentage content of sulfonylurea and imidazolinone herbicides residues in the soil solution varied depending on the nature of the active substance (maximum determined for imazapyr and lowest - metsulfuron-methyl) and soil type (more in acidic soil, compared to neutral and slightly alkaline soil). Effective management of pollution risks of the components of the natural environment (soil, surface and groundwater) provides a set of agrotechnological measures to reduce the number of large pores, voids and cracks in the arable layer. [ABSTRACT FROM AUTHOR]

Copyright of Revista Latinoamericana de Hipertension is the property of Revista Latinoamericana de Hipertension and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

The efficacy and safety of medications can be affected by alterations in gut microbiota in human beings. Among antidiabetic medications, incretin-based therapy such as dipeptidyl peptidase 4 inhibitors might affect gut microbiomes, which are related to glucose metabolism. This was a randomized, controlled, active-competitor study that aimed to compare the effects of combinations of gemigliptin–metformin vs. glimepiride–metformin as initial therapies on gut microbiota and glucose homeostasis in drug-naïve patients with type 2 diabetes. Seventy drug-naïve patients with type 2 diabetes (mean age, 52.2 years) with a glycated hemoglobin (HbA1c) level ≥7.5% were assigned to either gemigliptin–metformin or glimepiride–metformin combination therapies for 24 weeks. Changes in gut microbiota, biomarkers linked to glucose regulation, body composition, and amino acid blood levels were investigated. Although both treatments decreased the HbA1c levels significantly, the gemigliptin–metformin group achieved HbA1c ≤ 7.0% without hypoglycemia or weight gain more effectively than did the glimepiride–metformin group (59% vs. 24%; p < 0.05). At the phylum level, the Firmicutes/Bacteroidetes ratio tended to decrease after gemigliptin–metformin therapy (p = 0.065), with a notable depletion of taxa belonging to Firmicutes, including Lactobacillus, Ruminococcus torques, and Streptococcus (all p < 0.05). However, regardless of the treatment modality, a distinct difference in the overall gut microbiome composition was noted between patients who reached the HbA1c target goal and those who did not (p < 0.001). Treatment with gemigliptin–metformin resulted in a higher achievement of the glycemic target without hypoglycemia or weight gain, better than with glimepiride–metformin; these improvements might be related to beneficial changes in gut microbiota. [ABSTRACT FROM AUTHOR]

Ahmed Fouad Algendy,1 Ben Illigens,2 Ameena Alyazeedi3 1Clinical Pharmacy, Geriatric Department, Rumailah Hospital, Hamad Medical Corporation, Doha, Qatar; 2Dresden International University, Division of Health Care Sciences, Center for Clinical Research and Management Education, Dresden, Germany; 3Pharmacy Department, Rumailah Hospital, Hamad Medical Corporation, Doha, QatarCorrespondence: Ahmed Fouad Algendy, Pharmacy Department, Rumailah Hospital, Hamad Medical Corporation, PO 3050, Doha, Qatar, Tel +0097470094424, Fax +0097444397600, Email amohamed89@hamad.qaObjective: The main aim is to compare the risk of severe hypoglycemia associated with the modified-release (MR) gliclazide against glimepiride in diabetic older adults.Methods: All older adult diabetic patients who attended the emergency department (ED) between the 1st of Aug. 2017 and the end of Mar 2020 on gliclazide MR or glimepiride are included in two cohorts. We compared baseline differences between cohorts in demographics, lab results, diabetes complications, comorbidities, and drugs using the chi-squared test for categorical variables and unpaired t-test for continuous variables. All the baseline variables are used in a logistic regression to produce the propensity scores for receiving gliclazide MR. The primary outcome was Severe Hypoglycemia requiring Emergency Admission (SHEA). We used documented hypoglycemia, falls, fractures, Cardiovascular ED Admission (CVEA), and recurrent ED admissions as secondary outcomes. We used a univariate logistic regression followed by a propensity score-adjusted logistic regression to identify the adjusted odds ratio. We did a subgroup analysis for low and moderate-high doses users.Results: We included 2320 patients, 1786 were on gliclazide MR while 534 were on glimepiride. The risk of SHEA (Adjusted Odds Ratio AOR 6.74, p=0.002), falls (AOR 1.43, p=0.003), fractures (AOR 1.43, p=0.01), CVEA (AOR 1.66, p< 0.001), recurrent ED admission (AOR 1.39, p=0.002) were significantly higher. At the same time, documented hypoglycemia was insignificantly higher (AOR 1.17, p= 0.444) with gliclazide MR compared to glimepiride. The low doses of both treatments did not show any SHEA cases, while the results with higher doses showed the same pattern of increased risk with gliclazide MR as the principle analysis.Conclusion: Using gliclazide MR for older patients may not be a relatively safer alternative to avoid severe hypoglycemia and its possible consequences compared to glimepiride. It may be added to glimepiride in the Beers list of medications to be avoided in older adults.Keywords: sulfonylurea, diabetes, cardiovascular, falls, fractures

A 24-year-old man with diabetes mellitus presented with advanced kidney disease and severe proteinuria. Genetic testing revealed ABCC8-MODY12 (OMIM 600509), and a kidney biopsy showed nodular glomerulosclerosis. He commenced dialysis shortly thereafter, and glycemic control improved on treatment with a sulfonylurea. Diabetic end-stage kidney disease in patients with ABCC8-MODY12 has not been reported until now. Thus, our case highlights the risk for early-onset and severe diabetic kidney disease in patients with ABCC8-MODY12 and the importance of timely genetic diagnosis in unusual cases of diabetes to allow for proper treatment and prevention of late sequelae of diabetes.

IntroductionAdvanced liver disease with massive liver damage may affect the metabolism of hypoglycemic agents and increase the risk of hypoglycemia. We conduct this research to compare the risk of severe hypoglycemia between patients with type 2 diabetes, with and without compensated liver cirrhosis.MethodsFrom Taiwan’s National Health Insurance Research Database, we identified persons with type 2 diabetes with cirrhosis (n = 18,209) and without cirrhosis (n = 538,510) from January 1, 2000, to December 31, 2010. Cox proportional hazards models were adopted to assess risks of all-cause mortality and severe hypoglycemia.ResultsThe mean follow-up period of this study was 3.7 years. The incidence rates of death during follow-up were 26.54 and 2.75 per 1,000 patient-years [aHR 7.63 (6.70–8.70)] for patients with cirrhosis and without cirrhosis, respectively. The incidence rates of severe hypoglycemia during follow-up were 0.53 and 0.14 per 1,000 patient-years [aHR 2.74 (1.52–4.92)] for patients with and without cirrhosis, respectively. The subgroup analysis of hypoglycemia risks in patients with and without cirrhosis disclosed no significant interaction for variables such as age, sex, chronic kidney disease, sulfonylurea use, number of oral antidiabetic drugs, insulin, b-blocker, and fibrate.ConclusionThis cohort study demonstrated that patients with type 2 diabetes and compensated cirrhosis showed a higher risk of mortality and severe hypoglycemia than those without liver cirrhosis.

Aims/Introduction: Aging of society is accelerating in many countries. The purpose of this study was to describe the clinical features and sulfonylurea usage among diabetes outpatients aged ≥90 years (nonagenarians). Materials and Methods: This study was a retrospective observational study. The study population consisted of 69 nonagenarian diabetes outpatients and 857 diabetes outpatients aged <90 years. Patients were classified into four groups: group 1, <65 years; group 2, 65–74 years; group 3, 75–89 years; and group 4, ≥90 years. The presence of hypoglycemic episodes was defined as having self‐reported symptoms, or self‐monitored or clinically measured blood glucose level <70 mg/dL. Results: The median glycated hemoglobin (HbA1c) in group 1 and group 4 was 7.0% and 7.2%, respectively (P = 0.506). The proportion of sulfonylurea treatment in group 4 was 45.5%, which is significantly higher compared with the other three groups (20.0–27.8%, P < 0.001). In group 4, there was no difference between patients with or without sulfonylurea in age, sex, body mass index, HbA1c and number of antihyperglycemic agents. Five out of 25 nonagenarian sulfonylurea‐treated patients had hypoglycemic episodes within the last 2 years, their HbA1c were all 7.0 ≤ HbA1c < 8.0, and sulfonylurea or insulin was tapered in all cases after confirming hypoglycemia. Tapering dosage was attempted in all 25 sulfonylurea‐treated nonagenarian patients, but 15 needed to continue sulfonylurea for glycemic control, and 10 continued sulfonylurea with unknown reasons from their medical records. Conclusions: Although tapering the dosage of sulfonylurea was attempted in nonagenarian patients, sulfonylurea was widely continued for glycemic control. Reverse clinical inertia may exist in some sulfonylurea‐treated nonagenarian patients. [ABSTRACT FROM AUTHOR]

Based on the splicing method of active substructures, four chlorsulfuron derivatives (H01- H04) were designed and synthesized by introducing different sulfonylamino groups on the 5-position of the benzene ring, which were confirmed with melting point, ¹H NMR, 13C NMR and HRMS. The preliminary biological activity test results showed that the 5-sulfonylamino-substituted compounds exhibited good herbicidal activities. At concentration of 150 g a.i/hm², the inhibition rates against Brassica napus of H01, H02 and H04 were higher than 85% through pre-emergence treatment. In addition, the inhibition rates against Amaranthus retroflexus of H01 was 100%, which were better than chlorsulfuron (68.8%). For post-emergence treatment, the inhibition rates of H04 on B. napus and A. retroflexus were equivalent to that of chlorsulfuron. And the inhibition rates of H04 on Echinochloa crusgalli (85.2%) was better than that of chlorsulfuron (68.8%). The crop safety results indicated that the inhibition rates of these target compounds on the growth of wheat and corn were lower than that of chlrosulfuron. H01 and H04 showed safety to wheat growth through pre-emergence treatment. Additionally, the inhibition rates of H01-H04 on corn were lower than chlorsulfuron. In the case of post-emergence treatment, H01 and H04 showed safety to corn. Alkaline soil (pH 8.39) degradation results indicated that the DT50 (half-life of degradation) values of H01-H04 varied from 44.43 to 53.32 days, which was shorter than that of chlorsulfuron (157.53 days). Based on the results, H01 and H04 could be used as potential sulfonylurea herbicides on wheat and corn. This paper could provide a reference for the further design of new sulfonylurea herbicides with high herbicidal activity, rapid degradation rate and superior crop safety. [ABSTRACT FROM AUTHOR]

The aim of this study is to determine the clinical and molecular characteristics enabling differential diagnosis in a group of Turkish children clinically diagnosed with MODY and identify the cut-off value of HbA1c, which can distinguish patients with GCK variants from young-onset type 1 and type 2 diabetes. The study included 49 patients from 48 unrelated families who were admitted between 2018 and 2020 with a clinical diagnosis of MODY. Clinical and laboratory characteristics of the patients at the time of the diagnosis were obtained from hospital records. Variant analysis of ten MODY genes was performed using targeted next-generation sequencing (NGS) panel and the variants were classified according to American Collage of Medical Genetics and Genomics (ACMG) Standards and Guidelines recommendations. A total of 14 (28%) pathogenic/likely pathogenic variants were detected among 49 patients. 11 variants in GCK and 3 variants in HNF1A genes were found. We identified four novel variants in GCK gene. Using ROC analysis, we found that best cut-off value of HbA1c at the time of diagnosis for predicting the subjects with a GCK variant among patients suspected to have MODY was 6.95% (sensitivity 90%, specificity 86%, AUC 0.89 [95% CI: 0.783–1]). Most of the cases without GCK variant (33/38 [86%]) had an HbA1c value above this cutoff value. We found that among participants suspected of having MODY, family history, HbA1c at the time of diagnosis, and not using insulin therapy were the most differentiating variables of patients with GCK variants. Family history, HbA1c at the time of diagnosis, and not receiving insulin therapy were found to be the most distinguishing variables of patients with GCK variants among subjects suspected to have MODY. [ABSTRACT FROM AUTHOR]

BACKGROUND: Chlorsulfuron, metsulfuron‐methyl and ethametsulfuron can damage sensitive crops in rotation pattern as a result of their long persistence in soil. To explore novel sulfonylurea (SU) herbicides with favorable soil degradation rates, four series of SUs were synthesized through a structure‐based drug design (SBDD) strategy. RESULTS: The target compounds, especially Ia, Id and Ie, exhibited prospective herbicidal activity against dicotyledon oil seed rape (Brassica campestris), amaranth (Amaranthus retroflexus), monocotyledon barnyard grass (Echinochloa crusgalli) and crab grass (Digitaria sanguinalis) at a concentration of 15 a.i. g ha−1. Additionally, Ia, Id and Ig displayed excellent inhibitory effects against AtAHAS, with Kapp i values of 59.1, 34.5 and 71.8 μm, respectively, which were much lower than that of chlorsulfuron at 149.4 μm. The π‐π stack and H‐bonds between the Ia conformation and AtAHAS in the molecular docking results confirmed the series of compounds to be conventional AHAS inhibitors. In alkaline soil (pH = 8.46), compounds Ia–Ig revealed various degrees of acceleration in the degradation rate compared with chlorsulfuron. Besides, compound Ia showed considerable wheat and corn safety under postemergence at the concentration of 30, 60 and even 120 a.i. g ha−1. CONCLUSION: Overall, based on the synthetic procedure, herbicidal activity, soil degradation and crop safety, the Ia sulfonylureas series were chosen to be investigated as prospective AHAS inhibitors. The 5‐dimethylamino group on SUs accelerated the degradation rate at different levels in alkaline soils which seems to be controllable in conventional cropping systems in their further application. © 2022 Society of Chemical Industry. [ABSTRACT FROM AUTHOR]

Methods for protection of spring rapeseed from metsulfuron-methyl residues in soil using natural zeolite (clinoptilolite) and an organomineral complex of natural zeolite with humic substances have been proposed. Experiments arranged under controlled conditions of the Artificial Climate Laboratory have shown that the complete protection of crops, as well as stimulation of the plant development, can be provided by introducing zeolite into herbicide-contaminated soil with the further 6-week exposure prior to sowing. A presowing soil application of a complex of natural zeolite with humates at doses of 50 and 100 kg/ha not only completely neutralizes the phytotoxic effect of the herbicide (equal to 32.7%) but also stimulated plant growth up to 20% compared to control samples grown on herbicide-free soil. [ABSTRACT FROM AUTHOR]

Objective: To describe clinical presentation/longterm outcomes of patients with ABCC8/KCNJ11 variants in a large cohort of patients with diabetes. Research Design and Methods: We analyzed patients in the Diabetes Prospective Follow‐up (DPV) registry with diabetes and pathogenic variants in the ABCC8/KCNJ11 genes. For patients with available data at three specific time‐points—classification as K+‐channel variant, 2‐year follow‐up and most recent visit—the longitudinal course was evaluated in addition to the cross‐sectional examination. Results: We identified 93 cases with ABCC8 (n = 54)/KCNJ11 (n = 39) variants, 63 of them with neonatal diabetes. For 22 patients, follow‐up data were available. Of these, 19 were treated with insulin at diagnosis, and the majority of patients was switched to sulfonylurea thereafter. However, insulin was still administered in six patients at the most recent visit. Patients were in good metabolic control with a median (IQR) A1c level of 6.0% (5.5–6.7), that is, 42.1 (36.6–49.7) mmol/mol after 2 years and 6.7% (6.0–8.0), that is, 49.7 (42.1–63.9) mmol/mol at the most recent visit. Five patients were temporarily without medication for a median (IQR) time of 4.0 (3.5–4.4) years, while two other patients continue to be off medication at the last follow‐up. Conclusions: ABCC8/KCNJ11 variants should be suspected in children diagnosed with diabetes below the age of 6 months, as a high percentage can be switched from insulin to oral antidiabetic drugs. Thirty patients with diabetes due to pathogenic variants of ABCC8 or KCNJ11 were diagnosed beyond the neonatal period. Patients maintain good metabolic control even after a diabetes duration of up to 11 years. [ABSTRACT FROM AUTHOR]