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 ...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.展开更多
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 oc...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.展开更多
Sulfonylurea receptor(SUR) belongs to the adenosine 5′-triphosphate(ATP)-binding cassette(ABC) transporter family;however,SUR is associated with ion channels and acts as a regulatory subunit determining the opening o...Sulfonylurea receptor(SUR) belongs to the adenosine 5′-triphosphate(ATP)-binding cassette(ABC) transporter family;however,SUR is associated with ion channels and acts as a regulatory subunit determining the opening or closing of the pore.Abcc8 and Abcc9 genes code for the proteins SUR1 and SUR2,respectively.The SUR1 transcript encodes a protein of 1582 amino acids with a mass around 140–177 k Da expressed in the pancreas,brain,heart,and other tissues.It is well known that SUR1 assembles with Kir6.2 and TRPM4 to establish K_(ATP) channels and non-selective cation channels,respectively.Abbc8 and 9 are alternatively spliced,and the resulting transcripts encode different isoforms of SUR1 and SUR2,which have been detected by different experimental strategies.Interestingly,the use of binding assays to sulfonylureas and Western blotting has allowed the detection of shorter forms of SUR(-65 k Da).Identity of the SUR1 variants has not been clarified,and some authors have suggested that the shorter forms are unspecific.However,immunoprecipitation assays have shown that SUR2 short forms are part of a functional channel even coexisting with the typical forms of the receptor in the heart.This evidence confirms that the structure of the short forms of the SURs is fully functional and does not lose the ability to interact with the channels.Since structural changes in short forms of SUR modify its affinity to ATP,regulation of its expression might represent an advantage in pathologies where ATP concentrations decrease and a therapeutic target to induce neuroprotection.Remarkably,the expression of SUR1 variants might be induced by conditions associated to the decrease of energetic substrates in the brain(e.g.during stroke and epilepsy).In this review,we want to contribute to the knowledge of SUR1 complexity by analyzing evidence that shows the existence of short SUR1 variants and its possible implications in brain function.展开更多
Injury to the brain after intracerebral hemorrhage(ICH)results from numerous complex cellular mechanisms.At present,effective therapy for ICH is limited and a better understanding of the mechanisms of brain injury is ...Injury to the brain after intracerebral hemorrhage(ICH)results from numerous complex cellular mechanisms.At present,effective therapy for ICH is limited and a better understanding of the mechanisms of brain injury is necessary to improve prognosis.There is increasing evidence that ion channel dysregulation occurs at multiple stages in primary and secondary brain injury following ICH.Ion channels such as TWIK-related K+channel 1,sulfonylurea 1 transient receptor potential melastatin 4 and glutamate-gated channels affect ion homeostasis in ICH.They in turn participate in the formation of brain edema,disruption of the blood-brain barrier,and the generation of neurotoxicity.In this review,we summarize the interaction between ions and ion channels,the effects of ion channel dysregulation,and we discuss some therapeutics based on ion-channel modulation following ICH.展开更多
文摘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.
基金Supported by the Department of Science and Technology of Henan Province,China,No.222102310461。
文摘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.
基金supported by the CONACYT (FORDECYT-PRONACES/170733/2020 to PA and CB-2016-287959 to MRO)IAB is a doctoral student from Programa de Doctorado en Ciencias Biomédicas, Universidad Nacional Autónoma de México (UNAM)beneficiary of scholarship No. 275610 from CONACYT。
文摘Sulfonylurea receptor(SUR) belongs to the adenosine 5′-triphosphate(ATP)-binding cassette(ABC) transporter family;however,SUR is associated with ion channels and acts as a regulatory subunit determining the opening or closing of the pore.Abcc8 and Abcc9 genes code for the proteins SUR1 and SUR2,respectively.The SUR1 transcript encodes a protein of 1582 amino acids with a mass around 140–177 k Da expressed in the pancreas,brain,heart,and other tissues.It is well known that SUR1 assembles with Kir6.2 and TRPM4 to establish K_(ATP) channels and non-selective cation channels,respectively.Abbc8 and 9 are alternatively spliced,and the resulting transcripts encode different isoforms of SUR1 and SUR2,which have been detected by different experimental strategies.Interestingly,the use of binding assays to sulfonylureas and Western blotting has allowed the detection of shorter forms of SUR(-65 k Da).Identity of the SUR1 variants has not been clarified,and some authors have suggested that the shorter forms are unspecific.However,immunoprecipitation assays have shown that SUR2 short forms are part of a functional channel even coexisting with the typical forms of the receptor in the heart.This evidence confirms that the structure of the short forms of the SURs is fully functional and does not lose the ability to interact with the channels.Since structural changes in short forms of SUR modify its affinity to ATP,regulation of its expression might represent an advantage in pathologies where ATP concentrations decrease and a therapeutic target to induce neuroprotection.Remarkably,the expression of SUR1 variants might be induced by conditions associated to the decrease of energetic substrates in the brain(e.g.during stroke and epilepsy).In this review,we want to contribute to the knowledge of SUR1 complexity by analyzing evidence that shows the existence of short SUR1 variants and its possible implications in brain function.
基金supported by the National Natural Science Foundation of China(82071331,81870942,and 81520108011)the National Key Research and Development Program of China(2018YFC1312200)the Canadian Institutes of Health Research(VWY).
文摘Injury to the brain after intracerebral hemorrhage(ICH)results from numerous complex cellular mechanisms.At present,effective therapy for ICH is limited and a better understanding of the mechanisms of brain injury is necessary to improve prognosis.There is increasing evidence that ion channel dysregulation occurs at multiple stages in primary and secondary brain injury following ICH.Ion channels such as TWIK-related K+channel 1,sulfonylurea 1 transient receptor potential melastatin 4 and glutamate-gated channels affect ion homeostasis in ICH.They in turn participate in the formation of brain edema,disruption of the blood-brain barrier,and the generation of neurotoxicity.In this review,we summarize the interaction between ions and ion channels,the effects of ion channel dysregulation,and we discuss some therapeutics based on ion-channel modulation following ICH.
