Transient diabetes mellitus with ABCC8 variant successfully treated with sulfonylurea:Two case reports and review of literature

BACKGROUND Transient neonatal diabetes mellitus(TNDM)is a rare form of diabetes mellitus that usually presents within the first 6 mo of life.Patients often enter remission within several months,although relapse can occur later in life.Mutations in the ABCC8 gene,which encodes the sulfonylurea receptor 1 of the ATP-sensitive potassium channel in pancreatic beta cells,are associated with TNDM and permanent neonatal diabetes.This study describes a novel de novo c.3880C>T heterozygous ABCC8 variant that causes TNDM and can be treated with sulfonylurea therapy.CASE SUMMARY We retrospectively analyzed 2 Chinese patients with TNDM who were diagnosed,treated,or referred for follow-up between September 2017 and September 2023.The patients were tested for mutations using targeted next-generation sequencing.Patients with neonatal diabetes mellitus caused by a c.3880C>T heterozygous missense variant in the ABCC8 gene have not been reported before.Both children had an onset of post-infectious diabetic ketoacidosis,which is worth noting.At a follow-up visit after discontinuing insulin injection,oral glyburide was found to be effective with no adverse reactions.CONCLUSION Early genetic testing of neonatal diabetes mellitus aids in accurate diagnosis and treatment and helps avoid daily insulin injections that may cause pain.

Sulfonylurea类ALS/AHAS抑制剂作用方式的分子对接研究和新抑制剂的虚拟筛选

采用Dock5和Autodock3的组合,从乙酰乳酸合成酶(ALS)的晶体结构出发,对五个磺酰脲分子和三个类磺酰脲分子与ALS的相互作用方式进行了详细的分子对接研究,并结合对ALS与氯嘧磺隆(类磺酰脲)共结晶的复合物晶体结构的分析得出了一个简化的药效团模型,与前人利用其它手段得到的药效团模型一致.结合此药效团模型并根据sulfonylurea类分子与ALS的作用机理,我们对425个具有不同除草和杀虫作用的已知农药和ALS进行了分子对接研究和筛选,从中发现了一些可能对ALS有抑制作用的农药分子.此结果可以很好地解释这类农药的结构和活性的关系,对设计、开发新ALS抑制剂的先导化合物提供依据和指导.

Synthesis and Herbicidal Activity of Novel Sulfonylureas Containing Thiadiazol Moiety

Thirteen novel sulfonylureas containing thiadiazole moiety were synthesized in a two-step reaction. Their structures were determined using IR, ^1H NMR, HRFTMS, and elemental analysis. Herbicidal activities of these compounds were determined in the green house bio-assay. The results show that four compounds among them exhibit some activity toward four tested herbs.

Synthesis and Herbicidal Activity of Novel 5-Substituted Benzenesulfonylureas

Sulfonylurea herbicides have been widely used because of their low application rates, good crop sdeetivities and low mammalian toxicities. However, some sulfonylureas might persist unfavourably in the environment with residual problems. In order to look for ecologically safer and environmentally benign sulfonylureas, and on keeping the pyrimidine ring being monosubstitated, 15 novd C5-monosubstituted benzenesulfonylurea compounds were synthesized. The structures of all the compounds synthesized were confirmed by demental analysis and ^1H NMR. Preliminary herbicidal activities of these new sulfonylurea compounds were determined by ALS screening （ in vitro） and pot bioassay experiments（ in vivo）. The herbicidal results show that some novel sulfonylureas are comparable to commercial Foramsulfuron and Monosulfuron.

Development and molecular analysis of a novel acetohydroxyacid synthase rapeseed mutant with high resistance to sulfonylurea herbicides

With the increasing promotion of simplified rapeseed cultivation in recent years,the development of cultivars with high resistance to herbicides is urgently needed.We previously developed M342,which shows sulfonylurea herbicide resistance,by targeting acetohydroxyacid synthase(AHAS),a key enzyme in branched-chain amino acid synthesis.In the present study,we used a progeny line derived from M342 for an additional round of ethyl methane sulfonate mutagenesis,yielding the novel mutant DS3,which harbored two mutations in AHAS genes and showed high sulfonylurea resistance.One mutation was the substitution Trp574 Leu,as in M342,according to Arabidopsis protein sequencing.The other site was a newly recognized substitution,Pro197 Leu.A KASP marker targeting Pro197 Leu was developed and reliably predicted the response to sulfonylurea herbicides in the F2 population.The combination of Trp574 Leu and Pro197 Leu in DS3 produced a synergistic effect that greatly increased herbicide resistance.Analysis of the protein structures of AHAS1 and AHAS3 in wild-type and single-gene mutant plants revealed three-dimensional protein conformational changes that could account for differences in herbicide resistance characteristics including toxicity tolerance,AHAS enzyme activity,and AHAS gene expression.

Study on the bioactivity changes of hydroxylated sulfonylureas derivatives: A possible metabolism

Some new sulfonylureas and their hydroxylation products had been synthesized from 2-amino-4-methylpyrimidine. Their bioactivities against E. coli AHAS II in vitro were tested and the results indicated that the hydroxylation decreased the inhibition activities of sulfonylureas significantly. Subsequently herbicidal tests against stem-growth of barnyard grass and root-growth of rape confirmed the above conclusion. The preliminary molecular docking studies were also carried out to investigate the binding modes of non-hydroxylated and hydroxylated sulfonylureas with AHAS.

Metsulfuron-methyl Molecularly Imprinted Stir Bar Sorptive Extraction Coupled with High Performance Liquid Chromatography for Trace Sulfonylurea Herbicides Analysis in Complex Samples

Metsulfuron-methyl molecularly imprinted polymer（MIP）-coated stir bar was prepared for sorptive extraction of sulfonylurea herbicides in complex samples.The MIP-coating was about 21.3 μm thickness with the relative standard deviation（RSD） of 4.4%（n=10）.It was homogeneous and porous with good thermal stability and chemical stability.The extraction capability of the MIP-coating was 2.8 times over that of the non-imprinted polymer（NIP）-coating in hexane.The MIP-coating exhibited selective adsorption ability to the template and its analogues.The extraction conditions,including extraction solvent,desorption solvent,extraction time,desorption time and stirring speed,were optimized.A method for the determination of six sulfonylurea herbicides by MIP-coated stir bar sorptive extraction coupled with high performance liquid chromatography（HPLC） was developed.The linear range was 10―200 μg/L and the detection limits were within a range of 2.0―3.3 μg/L.It was also applied to the analysis of sulfonylurea herbicides in spiked river water,soil and rice samples.

Synthesis and Herbicidal Activity of Novel Sulfonylurea Derivatives

Sulfonylurea herbicides have been applied worldwide in agriculture. Some sulfonylurea residues might exist in soil longer than that people expected. However, flupyrsulfuron-methyl-sodium which was firstly reported as a new 5-substituted sulfonylurea herbicide has less than one month residual life. Therefore, 5-substituted benzenesulfonylureas are potential molecules to regulate its residual situation. In order to develop new sulfonylurea derivatives, the substituent on the critical 5-posotion of the benzene ring was optimized. On the basis of our former work on sulfonylureas which contains a characteristic mono-substituted pyrimidine moiety, twenty-six new sulfonylurea deriva- tives were synthesized and their structures were confirmed by 1H NMR, 31p NMR and elemental analysis. The greenhouse bioassay tests show that some title compounds exhibit potent herbicidal activity.

Synthesis and herbicidal activities of pyridyl sulfonylureas:More convenient preparation process of phenyl pyrimidylcarbamates

Four 4-monosubstituted pyrimidine pyridyl sulfonylureas were synthesized from pyridinesulfonamide and phenyl pyrimidylcarbamate and screened for herbicidal activities. We also reported a convenient preparation process of phenyl pyrimidylcarbamates from pyrimidineamine and phenyl chloroformate.

Roles of sulfonylurea receptor 1 and multidrug resistance protein 1 in modulating insulin secretion in human insulinoma

BACKGROUND:Sulfonylurea receptor 1(SUR1)and multidrug resistance protein 1(MRP1)are two prominent members of multidrug resistance proteins associated with insulin secretion. The aims of this study were to investigate their expression in insulinomas and their sole and synergistic effects in modulating abnormal insulin secretion. METHODS:Fasting glucose,insulin and C-peptide were measured in 11 insulinoma patients and 11 healthy controls. Prolonged oral glucose tolerance tests were performed in 6 insulinoma patients.Insulin content,SUR1 and MRP1 were detected in 11 insulinoma patients by immunohistochemistry. SUR1 and MRP1 were also detected in 6 insulinoma patients by immunofluorescence. RESULTS:Insulinoma patients presented the typical demons-trations of Whipple’s triad.Fasting glucose of each insulinoma patient was lower than 2.8 mmol/L,and simultaneous insulin and C-peptide were increased in insulinoma patients. Prolonged oral glucose tolerance tests showed that insulin secretion in insulinoma patients were also stimulated by high glucose.Immunohistochemistry and immunofluorescence staining showed that SUR1 increased,but MRP1 decreased in insulinoma compared with the adjacent islets. CONCLUSIONS:The hypersecretion of insulin in insulinomas might be,at least partially,due to the enrichment of SUR1. In contrast,MRP1,which is down-regulated in insulinomas, might reflect a negative feedback in insulin secretion.

Precise base editing of non-allelic acetolactate synthase genes confers sulfonylurea herbicide resistance in maize

Single-nucleotide polymorphisms contribute to phenotypic diversity in maize. Creation and functional annotation of point mutations has been limited by the low efficiency of conventional methods based on random mutation. An efficient tool for generating targeted single-base mutations is desirable for both functional genomics and precise genetic improvement. The objective of this study was to test the efficiency of targeted C-to-T base editing of two non-allelic acetolactate synthase(ALS) in generating sulfonylurea herbicide-resistant mutants. A CRISPR/Cas9 nickase-cytidine deaminase fused with uracil DNA glycosylase inhibitor(UGI) was employed to achieve targeted conversion of cytosine to thymine in ZmALS1 and ZmALS2. Both protoplasts and recovered mutant plants showed the activity of the cytosine base editor, with an in vivo efficiency of up to 13.8%. Transgene-free edited plants harboring a homozygous ZmALS1 mutation or a ZmALS1 and ZmALS2 double mutation were tested for their resistance at a dose of up to 15-fold the recommended limit of chlorsulfuron, a sulfonylurea herbicide widely used in agriculture. Targeted base editing of C-to-T per se and a phenotype verified in the generated mutants demonstrates the power of base editing in precise maize breeding.

Rapid Residue Analysis of Sulfonylurea Herbicides in Surface Water: Methodology and Residue Findings in eastern Tiaoxi River of China

A new method combining QuEChERS (quick, easy, cheap, effective, rugged and safe) and DLLME (dispersive liquid–liquid microextraction) for the simultaneous determination of residues of ten sulfonylurea herbicide in water using UPLC-MS/MS was developed and validated. Analytes were extracted and purified with QuEChERS and concentrated in chlorobenzene by applying the DLLME procedure. Several extraction parameters were tested, such as volume, extractive solvent by the QuEChERS method and subsequently used for DLLME, selection of extractive solvent and its volume, was tested. The developed method was validated on the basis of international guidelines. Mean recoveries ranged from 81.2 to 104.9%. Repeatability and reproducibility were lower than 10%. Limits of detection (LODs) and quantification (LOQs) were below 0.074 μg/L and 0.244 μg/L, respectively. Decision limit (CCα) and detection capability (CCβ) were calculated and CCβ ranged from 0.101 μg/L (pyrazosulfuron-ethyl) to 0.260 μg/L (nicosulfuron). Finally, when the method was applied to real samples, traces of three compounds were found in 42 samples and only thifensulfuon-methyl was detected above the LOQ in three samples at 0.17-0.20 μg/L.

Vildagliptin vs sulfonylurea in Indian Muslim diabetes patients fasting during Ramadan

AIM:To compare the use of vildagliptin and sulfonylurea with or without metformin in Indian Muslim patients with type 2 diabetes mellitus,fasting during Ramadan.METHODS:This was a 4-wk,multicenter,non-interventional,open-label,observational study.Incidence of hypoglycemic events(HEs),adverse events,and changes in glycosylated hemoglobin A1c(HbA1c),fasting plasma glucose,postprandial plasma glucose and body weight were measured pre-and post-Ramadan.RESULTS:Totally,97 patients were recruited and all completed the study(vildagliptin group,n=55;sulfonylurea group,n=42).HEs were reported in low frequencies in both the vildagliptin and the sulfonylurea groups[0 vs 2(4.8%)patients,respectively].Interestingly,HbA1c reduced by-0.43%(-4.71 mmol/mol)in the vildagliptin group[8.75%(72.10 mmol/mol)to8.32%(67.38 mmol/mol),P=0.009]while in the sulfonylurea group there was a small increase by 0.01%[0.08 mmol/mol;8.64%(70.92 mmol/mol)to 8.65%(71.00 mmol/mol),P=0.958].Higher percentage of vildagliptin-treated patients achieved HbA1c<7.0%(<53 mmol/mol)compared with sulfonylurea(16.4%vs4.8%).Mean decrease in the body weight was 1.2 kg and 0.03 kg,respectively(P<0.001).Both treatment groups were well tolerated during Ramadan.CONCLUSION:Vildagliptin is an attractive treatment option for Indian patients with type 2 diabetes mellitus who are fasting during Ramadan.

2D-and 3D-QSBR Study on the Relationship between the Structure and Biodegradation Property of Sulfonylurea Herbicides

Using DFT method, 10 sulfonylurea herbicides were computed at the B3LYP/6- 31G＊ level. Based on linear solvation energy theory, the corresponding linear solvation energy relationship （LSER） equation （R2 -- 0.759） to the half-life time （T1/2） of biodegradation was obtained with the structural and thermodynamic parameters as theoretical descriptors. Furthermore, CoMSIA method was also applied to establish 3D models which reveal the fields influencing these properties. The relationship between the properties and the structure was obtained. And the related coefficient of the model is 0.952. Results showed the electronic property is important to affect the biodegradation of these compounds by analysis of the 2D and 3D models.

Synthesis and Crystal Structure of a Sodium Monosulfuron-ester (N-[2'-(4-Methyl)pyrimidinyl]-2-carbomethoxy Benzyl Sulfonylurea Sodium)

Monosulfuron-ester is a novel sulfonylurea herbicide with ultra-low dosage Herein sodium monosulfuron-ester was synthesized and its crystal structure was determined by X-ray diffraction method. The title compound belongs to monoclinic, space group P21/c with a = 9.335（5）, b = 20.632（12）, c = 13.853（8） A, β = 107.193（9）°, Mr = 487.46, Z = 4, Dc = 1.270 g/cm^3, μ = 0.293 mm^-1, F（000） = 1015, R = 0.0859 and wR = 0.2633. In the title compound, Na coordinates with N（1）, O（1） and O（3） from one monosulfuron-ester molecule, N（4A） and O（5A） from the other monosulfuron-ester molecule and one oxygen atom from DMSO to give six coordination bonds.

Synthesis and Characterization of Novel Sulfonylurea Derivatives

On the basis of study on the mechanism of action of sulfonylurea herbicides, nine sulfonylurea derivatives of iso-{xazolidinone} were designed and synthesized. The structures of these compounds were confirmed by means of IR, MS, NMR and elemental analysis. The results of preliminary active tests indicate that the compounds have some herbicidal activity. The structure-activity relationship was also studied.

Certain sulfonylurea drugs increase serum free fatty acid in diabetic patients:A systematic review and meta-analysis

BACKGROUND Sulfonylurea(SU)is a commonly used antidiabetic drugs effective for type 2diabetes mellitus.Previous studies have reported that the SU treatment could alter the serum free fatty acid(FFA)concentration in diabetic patients;however,their exact effects remain unknown.AIM To assess the impact of SU on the FFA level in diabetic patients.METHODS A systematic literature search was conducted by consulting the PubMed,EMBASE,Cochrane Library,Reference Citation Analysis(https://www.referencecitationanalysis.com/),and Web of Science databases from January 1,1991 to July 30,2021.Either a fixed-effects model or random-effects model was applied to study the association between SU treatment and FFA concentration according to the heterogeneity test.Two investigators independently performed data extraction.The mean difference(MD)and corresponding 95%confidence interval(CI)were used to measure effect size.R3.5.1 software was utilized for conducting statistical analyses.RESULTS A total of 13 studies with 2273 individuals were selected.Results indicated that FFA concentration increased slightly after treatment with SU(MD=0.08,95%CI:0.03-0.12,P<0.01).In addition,we found that SU treatment combined with other antidiabetics could also increase the concentration of serum FFA(MD=0.14,95%CI:0.01-0.28,P<0.01).Regarding the type of SU,there was no significant difference in FFA concentration with glimepiride or glibenclamide.FFA concentration was higher at≥12 wk(MD=0.09,95%CI:0.04-0.13)but not at<12 wk(MD=0.01,95%CI:-0.07-0.09).CONCLUSION SU treatment could increase the serum FFA concentration in diabetic patients.The fundamental underlying mechanism still needs further investigation.

Marked Improvement in Glycemic Control with Exenatide on Addition to Metformin, Sulfonylurea and Insulin Glargine in Type 2 Diabetes Mellitus, a Real World Experience

Background: The major effect of Exenatide is attributed to lowering of post-prandial glycemia, whereas insulin glargine mainly improves fasting glycemia [FPG]. Objective: Therefore, we assessed effect of Exenatide administration at 6 months and for at 1 year on glycemic control, lipids, body weight [BW], daily insulin dose and hypoglycemic events. Methods: Records of 164 subjects, 126 men and 38 women administered Exenatide between January 2011 and December 2013 are included in this report. Exenatide was initiated at 5 mcg subcutaneously twice daily [BID] in obese subjects, BMI > 30 kg/m2, with C-peptide > 1 ng/d, and HbA1c 7.5% - 9.5%, while receiving daily metformin 2000 mg, Sulfonylurea Glimepiride 8 mg and insulin Glargine [GLAR]. Exclusion criteria were creatinine > 1.5 mg/dL and liver enzymes > 2.5 times upper limit of normal. Indices of glycemic control include fasting plasma glucose levels and HbA1c. Lipids include serum concentrations of total, LDL and HDL cholesterol. Other endpoints are body weight, daily insulin dose and number of hypoglycemic events per patient during 4 weeks prior to initiation of Exenatide, at 6 months and 1 year of therapy. Results: In 37 subjects, Exenatide was discontinued within 1 - 3 weeks;29 due to onset of nausea and vomiting. Seven of these also complained of abdominal pain and in these, serum amylase and lipase were elevated indicating presence of acute pancreatitis. One subject discontinued because of chest pain. Fasting plasma Glucose remained unchanged following Exenatide administration. However, HbA1c declined significantly denoting improvement in overall glycemic control without significant changes in body weight, daily insulin dose and hypoglycemic events. Lipid panel improved as well. Conclusion: Exenatide may be an appropriate adjuvant option in obese subjects with Type 2 diabetes mellitus with lack of desirable glycemic control while receiving therapy with Metformin, Glimepiride, and insulin Glargine. Moreover, improvement in glycemic control is likely to be secondary to lowering of post prandial hyperglycemia induced by Exenatide.

Sulfonylurea Glimepiride: A Proven Cost Effective, Safe and Reliable War Horse in Combating Hyperglycemia in Type 2 Diabetes

Recently, a debate has been raised regarding the place and the role of sulfonylureas (SU) amongst the armamentarium of drugs available for treatment of hyperglycemia in subjects with type 2 diabetes mellitus. With the advent of new drugs, SUs are being relegated and denigrated by some authorities contrary to present recommendations by various organizations e.g. American Diabetes Association, European Association for the Study of Diabetes and International Diabetes Federation. In this article, the advantages of SUs over the new agents in terms of their well established and proven better efficacy as well as their short term and long term (over 50 years) safety based on extensive literature data are documented. Moreover, lower costs of SUs render them to be far more cost effective when compared to new agents and therefore make them affordable in many regions of the world. Additionally, SUs are probably the initial drugs of choice in lean subjects with prediabetes and type 2 diabetes because they are the most effective secretogogues and major pathophysiologic mechanism of altered glucose metabolism in lean subjects is the decline in insulin secretion and not rising insulin resistance. Furthermore, SUs are also the most cost effective 2nd line agents in obese subjects with type 2 diabetes on lapse of glycemic control while receiving metformin. Finally, with progression of the disorder, the most cost effective combination of 2 oral agents in conjunction with basal insulin remains to be metformin and SUs. Many studies have documented a significantly greater extra pancreatic effect of glimepiride in comparison to other SUs probably because of its unique property in enhancing insulin sensitivity in conjunction with its ability to stimulate both 1st and 2nd phase insulin secretion. These characteristics may contribute to its greater efficacy with lesser hypoglycemia when compared with other SUs. Lack of hypoglycemic effect of metabolites of glimepiride may also be responsible for lesser hypoglycaemia. Moreover, metabolism of glimepiride performed partially by the liver and partially by the kidneys may render it suitable and adaptable to be administered safely in subjects with hepatic or renal dysfunctional as well as elderly. Finally, the documentation of its pleiotropic effects in lowering of cardiovascular surrogate markers, improving thrombotic milleau by reducing platelet aggregation factors along with improvement in glycemic control and its preferential binding to SU receptors on the pancreatic beta cells rather than myocardium may be responsible for providing better cardiovascular outcomes in comparison to other SUS and thus make it a better choice amongst SUs in subjects with or without presence of cardiovascular disease. Additionally, once daily administration because of lasting efficacy for 24 hours based on its half life is likely to enhance compliance on the part of patients and assist in attaining and maintaining desirable glycemic control. Therefore, SUs still deserve to be major players in management of hyperglycemia in subjects with type 2 diabetes mellitus and glimepiride may be the best choice amongst SUs because of its long term record regarding efficacy and safety in diverge population of subjects with type 2 diabetes mellitus.

QAAR exploration on pesticides with high solubility:An investigation on sulfonylurea herbicide dimers formed through π–π stacking interactions

Bioactive compounds could form aggregates that influence the bio-interactive processes. In this letter, based on π-π stacking models, quantitative aggregation-activity relationship （QAAR） studies were carried out on a series of sulfonylurea herbicides with good solubility. Four QAAR/QSAR models were constructed, which indicated that the bioactivity may strongly depend on both the characters of the dimeric aggregates and the monomer, The QAAR approach based on dimer-aggregates was also applicable for the highly water-soluble sulfonylurea herbicides that can form π-π stacking interactions. It was expected that the QAAR studies based on molecular aggregation state would be applied to other pesticide systems.