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Wu JX, Ding D, Chen L. The Emerging Structural Pharmacology of ATP-Sensitive Potassium Channels. Mol Pharmacol 2022; 102:234-239. [PMID: 36253099 DOI: 10.1124/molpharm.122.000570] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2022] [Accepted: 08/29/2022] [Indexed: 02/14/2025] Open
Abstract
ATP-sensitive potassium channels (KATP) are energy sensors that participate in a range of physiologic processes. These channels are also clinically validated drug targets. For decades, KATP inhibitors have been prescribed for diabetes and KATP activators have been used for the treatment of hypoglycemia, hypertension, and hair loss. In this Emerging Concepts article, we highlight our current knowledge about the drug binding modes observed using cryogenic electron microscopy techniques. The inhibitors and activators bind to two distinct sites in the transmembrane domain of the sulfonylurea receptor (SUR) subunit. We also discuss the possible mechanism of how these drugs allosterically modulate the dimerization of SUR nucleotide-binding domains (NBDs) and thus KATP channel activity. SIGNIFICANCE STATEMENT: ATP-sensitive potassium channels (KATP) are fundamental to energy homeostasis, and they participate in many vital physiological processes. KATP channels are important drug targets. Both KATP inhibitors (insulin secretagogues) and KATP activators are broadly used clinically for the treatment of related diseases. Recent cryogenic electron microscopy studies allow us to understand the emerging concept of KATP structural pharmacology.
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Affiliation(s)
- Jing-Xiang Wu
- State Key Laboratory of Membrane Biology, College of Future Technology, Institute of Molecular Medicine, Beijing Key Laboratory of Cardiometabolic Molecular Medicine (J.-X.W., D.D., L.C.), Peking-Tsinghua Center for Life Sciences (D.D., L.C.), Academy for Advanced Interdisciplinary Studies (D.D., L.C.), and National Biomedical Imaging Center, Peking University, Beijing, China (J.-X.W., D.D., L.C.)
| | - Dian Ding
- State Key Laboratory of Membrane Biology, College of Future Technology, Institute of Molecular Medicine, Beijing Key Laboratory of Cardiometabolic Molecular Medicine (J.-X.W., D.D., L.C.), Peking-Tsinghua Center for Life Sciences (D.D., L.C.), Academy for Advanced Interdisciplinary Studies (D.D., L.C.), and National Biomedical Imaging Center, Peking University, Beijing, China (J.-X.W., D.D., L.C.)
| | - Lei Chen
- State Key Laboratory of Membrane Biology, College of Future Technology, Institute of Molecular Medicine, Beijing Key Laboratory of Cardiometabolic Molecular Medicine (J.-X.W., D.D., L.C.), Peking-Tsinghua Center for Life Sciences (D.D., L.C.), Academy for Advanced Interdisciplinary Studies (D.D., L.C.), and National Biomedical Imaging Center, Peking University, Beijing, China (J.-X.W., D.D., L.C.)
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Tomlinson B, Patil NG, Fok M, Chan P, Lam CWK. The role of sulfonylureas in the treatment of type 2 diabetes. Expert Opin Pharmacother 2021; 23:387-403. [PMID: 34758676 DOI: 10.1080/14656566.2021.1999413] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/25/2022]
Abstract
INTRODUCTION Type 2 diabetes (T2D) is increasingly prevalent and associated with increased risk for cardiovascular and renal disease. After lifestyle modification, metformin is usually the first-line pharmacotherapy and sulfonylureas are traditionally added after metformin failure. However, with newer glucose lowering drugs that may have less risk of hypoglycemia or that may reduce cardiovascular and renal events, the position of sulfonylureas is being reevaluated. AREAS COVERED In this article, the authors review relevant publications related to the use of sulfonylureas. EXPERT OPINION Sulfonylureas are potent glucose lowering drugs. The risk of hypoglycemia varies with different drugs within the class and can be minimized by using the safer drugs, possibly in lower doses. Cardiovascular events do not appear to be increased with some of the newer generation drugs. The durability of glycemic control also appears comparable to other newer agents. Sulfonylureas are the preferred treatment for some types of monogenic diabetes and selection of T2D patients who may have greater benefit from sulfonylureas based on certain phenotypes and genotypes is likely to be refined further by precision medicine. Sulfonylureas are inexpensive and readily available everywhere and they are still the most frequently used second-line treatment for T2D in many parts of the world.
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Affiliation(s)
- Brian Tomlinson
- Faculty of Medicine, Macau University of Science and Technology, Macau, China
| | | | - Manson Fok
- Faculty of Medicine, Macau University of Science and Technology, Macau, China
| | - Paul Chan
- Division of Cardiovascular Medicine, Department of Internal Medicine, Wan Fang Hospital, Taipei Medical University, Taipei City, Taiwan
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Ding D, Wang M, Wu JX, Kang Y, Chen L. The Structural Basis for the Binding of Repaglinide to the Pancreatic K ATP Channel. Cell Rep 2020; 27:1848-1857.e4. [PMID: 31067468 DOI: 10.1016/j.celrep.2019.04.050] [Citation(s) in RCA: 64] [Impact Index Per Article: 12.8] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2019] [Revised: 03/15/2019] [Accepted: 04/10/2019] [Indexed: 01/13/2023] Open
Abstract
Repaglinide (RPG) is a short-acting insulin secretagogue widely prescribed for the treatment of type 2 diabetes. It boosts insulin secretion by inhibiting the pancreatic ATP-sensitive potassium channel (KATP). However, the mechanisms by which RPG binds to the KATP channel are poorly understood. Here, we describe two cryo-EM structures: the pancreatic KATP channel in complex with inhibitory RPG and adenosine-5'-(γ-thio)-triphosphate (ATPγS) at 3.3 Å and a medium-resolution structure of a RPG-bound mini SUR1 protein in which the N terminus of the inward-rectifying potassium channel 6.1 (Kir6.1) is fused to the ABC transporter module of the sulfonylurea receptor 1 (SUR1). These structures reveal the binding site of RPG in the SUR1 subunit. Furthermore, the high-resolution structure reveals the complex architecture of the ATP binding site, which is formed by both Kir6.2 and SUR1 subunits, and the domain-domain interaction interfaces.
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Affiliation(s)
- Dian Ding
- State Key Laboratory of Membrane Biology, Institute of Molecular Medicine, Peking University, Beijing Key Laboratory of Cardiometabolic Molecular Medicine, Beijing 100871, China; Peking-Tsinghua Center for Life Sciences, Peking University, Beijing 100871, China; Academy for Advanced Interdisciplinary Studies, Peking University, Beijing 100871, China
| | - Mengmeng Wang
- State Key Laboratory of Membrane Biology, Institute of Molecular Medicine, Peking University, Beijing Key Laboratory of Cardiometabolic Molecular Medicine, Beijing 100871, China; Peking-Tsinghua Center for Life Sciences, Peking University, Beijing 100871, China; Academy for Advanced Interdisciplinary Studies, Peking University, Beijing 100871, China
| | - Jing-Xiang Wu
- State Key Laboratory of Membrane Biology, Institute of Molecular Medicine, Peking University, Beijing Key Laboratory of Cardiometabolic Molecular Medicine, Beijing 100871, China; Peking-Tsinghua Center for Life Sciences, Peking University, Beijing 100871, China
| | - Yunlu Kang
- State Key Laboratory of Membrane Biology, Institute of Molecular Medicine, Peking University, Beijing Key Laboratory of Cardiometabolic Molecular Medicine, Beijing 100871, China
| | - Lei Chen
- State Key Laboratory of Membrane Biology, Institute of Molecular Medicine, Peking University, Beijing Key Laboratory of Cardiometabolic Molecular Medicine, Beijing 100871, China; Peking-Tsinghua Center for Life Sciences, Peking University, Beijing 100871, China.
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4
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Martin GM, Sung MW, Shyng SL. Pharmacological chaperones of ATP-sensitive potassium channels: Mechanistic insight from cryoEM structures. Mol Cell Endocrinol 2020; 502:110667. [PMID: 31821855 PMCID: PMC6994177 DOI: 10.1016/j.mce.2019.110667] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/18/2019] [Revised: 11/22/2019] [Accepted: 11/22/2019] [Indexed: 02/07/2023]
Abstract
ATP-sensitive potassium (KATP) channels are uniquely evolved protein complexes that couple cell energy levels to cell excitability. They govern a wide range of physiological processes including hormone secretion, neuronal transmission, vascular dilation, and cardiac and neuronal preconditioning against ischemic injuries. In pancreatic β-cells, KATP channels composed of Kir6.2 and SUR1, encoded by KCNJ11 and ABCC8, respectively, play a key role in coupling blood glucose concentration to insulin secretion. Mutations in ABCC8 or KCNJ11 that diminish channel function result in congenital hyperinsulinism. Many of these mutations principally hamper channel biogenesis and hence trafficking to the cell surface. Several small molecules have been shown to correct channel biogenesis and trafficking defects. Here, we review studies aimed at understanding how mutations impair channel biogenesis and trafficking and how pharmacological ligands overcome channel trafficking defects, particularly highlighting recent cryo-EM structural studies which have shed light on the mechanisms of channel assembly and pharmacological chaperones.
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Affiliation(s)
- Gregory M Martin
- Department of Chemical Physiology and Biochemistry, Oregon Health & Science University, Portland, OR, 97239, USA
| | - Min Woo Sung
- Department of Chemical Physiology and Biochemistry, Oregon Health & Science University, Portland, OR, 97239, USA
| | - Show-Ling Shyng
- Department of Chemical Physiology and Biochemistry, Oregon Health & Science University, Portland, OR, 97239, USA.
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Wu JX, Ding D, Wang M, Chen L. Structural Insights into the Inhibitory Mechanism of Insulin Secretagogues on the Pancreatic ATP-Sensitive Potassium Channel. Biochemistry 2019; 59:18-25. [PMID: 31566370 DOI: 10.1021/acs.biochem.9b00692] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/08/2023]
Abstract
Sulfonylureas and glinides are commonly used oral insulin secretagogues (ISs) that act on the pancreatic ATP-sensitive potassium (KATP) channel to promote insulin secretion in order to lower the blood glucose level. Physiologically, KATP channels are inhibited by intracellular ATP and activated by Mg-ADP. Therefore, they sense the cellular energy status to regulate the permeability of potassium ions across the plasma membrane. The pancreatic KATP channel is composed of the pore-forming Kir6.2 subunits and the regulatory SUR1 subunits. Previous electrophysiological studies have established that ISs bind to the SUR1 subunit and inhibit the channel activity primarily by two mechanisms. First, ISs prevent Mg-ADP activation. Second, ISs inhibit the channel activity of Kir6.2 directly. Several cryo-EM structures of the pancreatic KATP channel determined recently have provided remarkable structural insights into these two mechanisms.
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Affiliation(s)
- Jing-Xiang Wu
- State Key Laboratory of Membrane Biology, Beijing Key Laboratory of Cardiometabolic Molecular Medicine, Institute of Molecular Medicine , Peking University , Beijing 100871 , China.,Peking-Tsinghua Center for Life Sciences , Peking University , Beijing 100871 , China
| | - Dian Ding
- State Key Laboratory of Membrane Biology, Beijing Key Laboratory of Cardiometabolic Molecular Medicine, Institute of Molecular Medicine , Peking University , Beijing 100871 , China.,Peking-Tsinghua Center for Life Sciences , Peking University , Beijing 100871 , China.,Academy for Advanced Interdisciplinary Studies , Peking University , Beijing 100871 , China
| | - Mengmeng Wang
- State Key Laboratory of Membrane Biology, Beijing Key Laboratory of Cardiometabolic Molecular Medicine, Institute of Molecular Medicine , Peking University , Beijing 100871 , China.,Peking-Tsinghua Center for Life Sciences , Peking University , Beijing 100871 , China.,Academy for Advanced Interdisciplinary Studies , Peking University , Beijing 100871 , China
| | - Lei Chen
- State Key Laboratory of Membrane Biology, Beijing Key Laboratory of Cardiometabolic Molecular Medicine, Institute of Molecular Medicine , Peking University , Beijing 100871 , China.,Peking-Tsinghua Center for Life Sciences , Peking University , Beijing 100871 , China
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Xu H, Yang Y, Chen Y, Mueller U, Iyer S, Presland J, Yang R, Kariv I. Determination of EPAC2 function using EPAC2 null Min6 sublines generated through CRISPR-Cas9 technology. Mol Cell Endocrinol 2018; 473:114-123. [PMID: 29407196 DOI: 10.1016/j.mce.2018.01.010] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/07/2017] [Revised: 01/16/2018] [Accepted: 01/17/2018] [Indexed: 11/21/2022]
Abstract
Min6 cells, a mouse β cell line derived from transgenic mouse expressing the large T-antigen of SV40 in pancreatic beta cells, are commonly utilized as an in vitro cellular model for investigating targets involved in insulin secretion. Epac2, an exchange protein that can be directly activated by cyclic AMP (cAMP), is critical for pharmacologic stimuli-induced insulin secretion and has been hypothesized to be a direct target of sulfonylurea. Previous loss of function studies only specifically knocked out EPAC2 isoform A, leaving the other two isoforms intact. In this study, we investigated the function of EPAC2 in Min6 cells by generating EPAC2 knock-out sublines using CRISPR-Cas9 technology, by removing all three isoforms of EPAC2. Our results indicate that Min6 cells can be successfully cloned from a single cell after electroporation with plasmids expressing EPAC2 specific guide RNA, Cas9 and GFP, followed by sorting for GFP expressing single cells. Two clones were found to have a single nucleotide deletion in targeted site of EPAC2 gene by sequencing, therefore creating a frame shift in exon 13. The EPAC2 null clones have an unexpectedly increased secretion of insulin at basal level and an elevated total intracellular insulin content. However, EPAC2 deficiency impaires glucose and sulfonylurea induced insulin secretion without affecting sulfonylurea binding to cells. Potassium chloride induced insulin secretion remains intact. Interestingly, cAMP levels remained unchanged in EPAC2 null cells during these processes. To understand the global function of EPAC2, RNA Seq study was performed, which reveals that EPAC2 deficiency affects expression of multiple previously unrecognized genes, suggesting that EPAC2 can function through multiple pathways in addition to being a cAMP sensor.
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Affiliation(s)
- Haiyan Xu
- Department of Early Discovery Pharmacology, Cellular Pharmacology, Merck & Co., Inc., 33 Ave. Louis Pasteur, Boston, MA 02115, USA.
| | - Yi Yang
- Department of Early Discovery Pharmacology, Cellular Pharmacology, Merck & Co., Inc., 33 Ave. Louis Pasteur, Boston, MA 02115, USA
| | - Yiping Chen
- Department of Early Discovery Pharmacology, Cellular Pharmacology, Merck & Co., Inc., 33 Ave. Louis Pasteur, Boston, MA 02115, USA
| | - Uwe Mueller
- Department of Early Discovery Pharmacology, Cellular Pharmacology, Merck & Co., Inc., 33 Ave. Louis Pasteur, Boston, MA 02115, USA
| | - Sharanya Iyer
- Department of Early Discovery Pharmacology, Cellular Pharmacology, Merck & Co., Inc., 33 Ave. Louis Pasteur, Boston, MA 02115, USA
| | - Jeremy Presland
- Department of Early Discovery Pharmacology, Cellular Pharmacology, Merck & Co., Inc., 33 Ave. Louis Pasteur, Boston, MA 02115, USA
| | - Ruojing Yang
- Department of Early Discovery Pharmacology, Cellular Pharmacology, Merck & Co., Inc., 33 Ave. Louis Pasteur, Boston, MA 02115, USA
| | - Ilona Kariv
- Department of Early Discovery Pharmacology, Cellular Pharmacology, Merck & Co., Inc., 33 Ave. Louis Pasteur, Boston, MA 02115, USA
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Martin GM, Kandasamy B, DiMaio F, Yoshioka C, Shyng SL. Anti-diabetic drug binding site in a mammalian K ATP channel revealed by Cryo-EM. eLife 2017; 6:31054. [PMID: 29035201 PMCID: PMC5655142 DOI: 10.7554/elife.31054] [Citation(s) in RCA: 107] [Impact Index Per Article: 13.4] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2017] [Accepted: 10/11/2017] [Indexed: 12/25/2022] Open
Abstract
Sulfonylureas are anti-diabetic medications that act by inhibiting pancreatic KATP channels composed of SUR1 and Kir6.2. The mechanism by which these drugs interact with and inhibit the channel has been extensively investigated, yet it remains unclear where the drug binding pocket resides. Here, we present a cryo-EM structure of a hamster SUR1/rat Kir6.2 channel bound to a high-affinity sulfonylurea drug glibenclamide and ATP at 3.63 Å resolution, which reveals unprecedented details of the ATP and glibenclamide binding sites. Importantly, the structure shows for the first time that glibenclamide is lodged in the transmembrane bundle of the SUR1-ABC core connected to the first nucleotide binding domain near the inner leaflet of the lipid bilayer. Mutation of residues predicted to interact with glibenclamide in our model led to reduced sensitivity to glibenclamide. Our structure provides novel mechanistic insights of how sulfonylureas and ATP interact with the KATP channel complex to inhibit channel activity.
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Affiliation(s)
- Gregory M Martin
- Department of Biochemistry and Molecular Biology, Oregon Health and Science University, Portland, United States
| | - Balamurugan Kandasamy
- Department of Biochemistry and Molecular Biology, Oregon Health and Science University, Portland, United States
| | - Frank DiMaio
- Department of Biochemistry, University of Washington, Seattle, United States
| | - Craig Yoshioka
- Department of Biomedical Engineering, Oregon Health and Science University, Portland, United States
| | - Show-Ling Shyng
- Department of Biochemistry and Molecular Biology, Oregon Health and Science University, Portland, United States
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8
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Fatehi M, Carter CC, Youssef N, Light PE. The mechano-sensitivity of cardiac ATP-sensitive potassium channels is mediated by intrinsic MgATPase activity. J Mol Cell Cardiol 2017; 108:34-41. [PMID: 28483598 DOI: 10.1016/j.yjmcc.2017.05.004] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/05/2017] [Revised: 05/03/2017] [Accepted: 05/04/2017] [Indexed: 10/19/2022]
Abstract
Cardiac ATP-sensitive K+ (KATP) channel activity plays an important cardio-protective role in regulating excitability in response to metabolic stress. Evidence suggests that these channels are also mechano-sensitive and therefore may couple KATP channel activity to increased cardiac workloads. However, the molecular mechanism that couples membrane stretch to channel activity is not currently known. We hypothesized that membrane stretch may alter the intrinsic MgATPase activity of the cardiac KATP channel resulting in increased channel activation. The inside-out patch-clamp technique was used to record single-channel and macroscopic recombinant KATP channel activity in response to membrane stretch elicited by negative pipette pressure. We found that stretch activation requires the presence of the SUR subunit and that inhibition of MgATPase activity with either the non-hydrolysable ATP analog AMP-PNP or the ATPase inhibitor BeFx significantly reduced the stimulatory effect of stretch. We employed a point mutagenic approach to determine that a single residue (K1337) in the hairpin loop proximal to the major MgATPase catalytic site in the SUR2A subunit is responsible for the difference in mechano-sensitivity between SUR2A and SUR1 containing KATP channels. Moreover, using a double cysteine mutant substitution in the hairpin loop region revealed the importance of a key residue-residue interaction in this region that transduces membrane mechanical forces into KATP channel stimulation via increases in channel MgATPase activity. With respect to KATP channel pharmacology, glibenclamide, but not glicalizide or repaglinide, was able to completely inhibit KATP channel mechano-sensitivity. In summary, our results provide a highly plausible molecular mechanism by which mechanical membrane forces are rapidly converted in changes in KATP channel activity that have implications for our understanding of cardiac KATP channels in physiological or pathophysiological settings that involve increased workload.
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Affiliation(s)
- Mohammad Fatehi
- Department of Pharmacology, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, Alberta T6G 2E1, Canada
| | - Christian C Carter
- Department of Pharmacology, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, Alberta T6G 2E1, Canada
| | - Nermeen Youssef
- Department of Pharmacology, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, Alberta T6G 2E1, Canada
| | - Peter E Light
- Department of Pharmacology, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, Alberta T6G 2E1, Canada.
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Deacon CF, Lebovitz HE. Comparative review of dipeptidyl peptidase-4 inhibitors and sulphonylureas. Diabetes Obes Metab 2016; 18:333-47. [PMID: 26597596 DOI: 10.1111/dom.12610] [Citation(s) in RCA: 147] [Impact Index Per Article: 16.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/08/2015] [Revised: 11/18/2015] [Accepted: 11/18/2015] [Indexed: 12/16/2022]
Abstract
Type 2 diabetes (T2DM) is a progressive disease, and pharmacotherapy with a single agent does not generally provide durable glycaemic control over the long term. Sulphonylurea (SU) drugs have a history stretching back over 60 years, and have traditionally been the mainstay choice as second-line agents to be added to metformin once glycaemic control with metformin monotherapy deteriorates; however, they are associated with undesirable side effects, including increased hypoglycaemia risk and weight gain. Dipeptidyl peptidase (DPP)-4 inhibitors are, by comparison, more recent, with the first compound being launched in 2006, but the class now globally encompasses at least 11 different compounds. DPP-4 inhibitors improve glycaemic control with similar efficacy to SUs, but do not usually provoke hypoglycaemia or weight gain, are relatively free from adverse side effects, and have recently been shown not to increase cardiovascular risk in large prospective safety trials. Because of these factors, DPP-4 inhibitors have become an established therapy for T2DM and are increasingly being positioned earlier in treatment algorithms. The present article reviews these two classes of oral antidiabetic drugs (DPP-4 inhibitors and SUs), highlighting differences and similarities between members of the same class, as well as discussing the potential advantages and disadvantages of the two drug classes. While both classes have their merits, the choice of which to use depends on the characteristics of each individual patient; however, for the majority of patients, DPP-4 inhibitors are now the preferred choice.
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Affiliation(s)
- C F Deacon
- Department of Biomedical Sciences, University of Copenhagen, Copenhagen N, Denmark
| | - H E Lebovitz
- State University of New York Health Science Center, Brooklyn, NY, USA
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Kalra S, Aamir AH, Raza A, Das AK, Azad Khan AK, Shrestha D, Qureshi MF, Md Fariduddin, Pathan MF, Jawad F, Bhattarai J, Tandon N, Somasundaram N, Katulanda P, Sahay R, Dhungel S, Bajaj S, Chowdhury S, Ghosh S, Madhu SV, Ahmed T, Bulughapitiya U. Place of sulfonylureas in the management of type 2 diabetes mellitus in South Asia: A consensus statement. Indian J Endocrinol Metab 2015; 19:577-96. [PMID: 26425465 PMCID: PMC4566336 DOI: 10.4103/2230-8210.163171] [Citation(s) in RCA: 65] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/22/2022] Open
Abstract
Since their introduction in clinical practice in the 1950's, Sulfonylureas (SUs) have remained the main-stay of pharmacotherapy in the management of type 2 diabetes. Despite their well-established benefits, their place in therapy is inappropriately being overshadowed by newer therapies. Many of the clinical issues associated with the use of SUs are agent-specific, and do not pertain to the class as such. Modern SUs (glimepiride, gliclazide MR) are backed by a large body of evidence, experience, and most importantly, outcome data, which supports their role in managing patients with diabetes. Person-centred care, i.e., careful choice of SU, appropriate dosage, timing of administration, and adequate patient counseling, will ensure that deserving patients are not deprived of the advantages of this well-established class of anti-diabetic agents. Considering their efficacy, safety, pleiotropic benefits, and low cost of therapy, SUs should be considered as recommended therapy for the treatment of diabetes in South Asia. This initiative by SAFES aims to encourage rational, safe and smart prescription of SUs, and includes appropriate medication counseling.
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Affiliation(s)
- Sanjay Kalra
- Department of Endocrinology, Bharti Hospital and BRIDE, Karnal, Haryana, India
| | - A H Aamir
- Department of Endocrinology, Post Graduate Medical Institute Hayatabad Medical Complex, Peshawar, Pakistan
| | - Abbas Raza
- Shaukat Khanum Memorial Cancer Hospital and Research Centre, Lahore, Pakistan
| | - A K Das
- Department of Endocrinology, Pondicherry Institute of Medical Sciences, Puducherry, India
| | - A K Azad Khan
- Department of Public Health, Bangladesh University of Health Sciences, Dhaka, Bangladesh
| | - Dina Shrestha
- Department of Endocrinology, Norvic International Hospital, Kathmandu, Nepal
| | - Md Faisal Qureshi
- Department of Endocrinology, Al-Khaliq Medicare Hospital, Dhaka, Bangladesh
| | - Md Fariduddin
- Department of Endocrinology, Bangabandhu Sheikh Mujib Medical University, Shahbag, Dhaka, Bangladesh
| | | | - Fatema Jawad
- Department of Diabetology, Medilink Clinics, Karachi, Pakistan
| | - Jyoti Bhattarai
- Department of Medicine, Trivuvan University, Kathmandu, Nepal
| | - Nikhil Tandon
- Department of Endocrinology and Metabolism, All India Institute of Medical Sciences, Ansari Nagar, New Delhi, India
| | - Noel Somasundaram
- South Asian Federation of Endocrine Societies, National Hospital, Dhaka, Bangladesh
| | - Prasad Katulanda
- Department of Clinical Medicines, Diabetes Research Unit, University of Colombo, Colombo, Sri Lanka
| | - Rakesh Sahay
- Department of Endocrinology, Osmania Medical College, Hyderabad, Telangana, India
| | - Sanjib Dhungel
- Department of Medicine, Nepal Medical College Teaching Hospital, Kathmandu, Nepal
| | - Sarita Bajaj
- Department of Medicine, MLN Medical College, Allahabad, Uttar Pradesh, India
| | - Subhankar Chowdhury
- Department of Endocrinology, IPGMER and SSKM Hospital, Kolkata, West Bengal, India
| | - Sujoy Ghosh
- Department of Endocrinology and Metabolism, IPGMER, Kolkata, West Bengal, India
| | - S V Madhu
- Department of Medicine and Head, Centre for Diabetes, Endocrinology and Metabolism, UCMS-GTB Hospital, New Delhi, India
| | - Tofail Ahmed
- Department of Endocrinology, BIRDEM, Dhaka, Bangladesh
| | - Uditha Bulughapitiya
- Department of Endocrinology, Kalubowila South Teaching Hospital, Kalubowila, Sri Lanka
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Sun R, Liu C, Zhang H, Wang Q. Benzoylurea Chitin Synthesis Inhibitors. JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY 2015; 63:6847-65. [PMID: 26168369 DOI: 10.1021/acs.jafc.5b02460] [Citation(s) in RCA: 78] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/28/2023]
Abstract
Benzoylurea chitin synthesis inhibitors are widely used in integrated pest management (IPM) and insecticide resistance management (IRM) programs due to their low toxicity to mammals and predatory insects. In the past decades, a large number of benzoylurea derivatives have been synthesized, and 15 benzoylurea chitin synthesis inhibitors have been commercialized. This review focuses on the history of commercial benzolyphenylureas (BPUs), synthetic methods, structure-activity relationships (SAR), action mechanism research, environmental behaviors, and ecotoxicology. Furthermore, their disadvantages of high risk to aquatic invertebrates and crustaceans are pointed out. Finally, we propose that the para-substituents at anilide of benzoylphenylureas should be the functional groups, and bipartite model BPU analogues are discussed in an attempt to provide new insight for future development of BPUs.
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Affiliation(s)
- Ranfeng Sun
- §State Key Laboratory of Elemento-Organic Chemistry, Institute of Elemento-Organic Chemistry, Collaborative Innovation Center of Chemical Science and Engineering (Tianjin), Nankai University, Tianjin 300071, People's Republic of China
| | | | | | - Qingmin Wang
- §State Key Laboratory of Elemento-Organic Chemistry, Institute of Elemento-Organic Chemistry, Collaborative Innovation Center of Chemical Science and Engineering (Tianjin), Nankai University, Tianjin 300071, People's Republic of China
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12
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Proks P, de Wet H, Ashcroft FM. Sulfonylureas suppress the stimulatory action of Mg-nucleotides on Kir6.2/SUR1 but not Kir6.2/SUR2A KATP channels: a mechanistic study. ACTA ACUST UNITED AC 2015; 144:469-86. [PMID: 25348414 PMCID: PMC4210431 DOI: 10.1085/jgp.201411222] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/25/2022]
Abstract
Sulfonylureas suppress the stimulatory effect of Mg-nucleotides on recombinant β-cell (Kir6.2/SUR1) but not cardiac (Kir6.2/SUR2A) KATP channels. Sulfonylureas, which stimulate insulin secretion from pancreatic β-cells, are widely used to treat both type 2 diabetes and neonatal diabetes. These drugs mediate their effects by binding to the sulfonylurea receptor subunit (SUR) of the ATP-sensitive K+ (KATP) channel and inducing channel closure. The mechanism of channel inhibition is unusually complex. First, sulfonylureas act as partial antagonists of channel activity, and second, their effect is modulated by MgADP. We analyzed the molecular basis of the interactions between the sulfonylurea gliclazide and Mg-nucleotides on β-cell and cardiac types of KATP channel (Kir6.2/SUR1 and Kir6.2/SUR2A, respectively) heterologously expressed in Xenopus laevis oocytes. The SUR2A-Y1206S mutation was used to confer gliclazide sensitivity on SUR2A. We found that both MgATP and MgADP increased gliclazide inhibition of Kir6.2/SUR1 channels and reduced inhibition of Kir6.2/SUR2A-Y1206S. The latter effect can be attributed to stabilization of the cardiac channel open state by Mg-nucleotides. Using a Kir6.2 mutation that renders the KATP channel insensitive to nucleotide inhibition (Kir6.2-G334D), we showed that gliclazide abolishes the stimulatory effects of MgADP and MgATP on β-cell KATP channels. Detailed analysis suggests that the drug both reduces nucleotide binding to SUR1 and impairs the efficacy with which nucleotide binding is translated into pore opening. Mutation of one (or both) of the Walker A lysines in the catalytic site of the nucleotide-binding domains of SUR1 may have a similar effect to gliclazide on MgADP binding and transduction, but it does not appear to impair MgATP binding. Our results have implications for the therapeutic use of sulfonylureas.
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Affiliation(s)
- Peter Proks
- Oxford Centre for Gene Function and Department of Physiology, Anatomy, and Genetics, University of Oxford, Oxford OX1 3PT, England, UK Oxford Centre for Gene Function and Department of Physiology, Anatomy, and Genetics, University of Oxford, Oxford OX1 3PT, England, UK
| | - Heidi de Wet
- Oxford Centre for Gene Function and Department of Physiology, Anatomy, and Genetics, University of Oxford, Oxford OX1 3PT, England, UK Oxford Centre for Gene Function and Department of Physiology, Anatomy, and Genetics, University of Oxford, Oxford OX1 3PT, England, UK
| | - Frances M Ashcroft
- Oxford Centre for Gene Function and Department of Physiology, Anatomy, and Genetics, University of Oxford, Oxford OX1 3PT, England, UK Oxford Centre for Gene Function and Department of Physiology, Anatomy, and Genetics, University of Oxford, Oxford OX1 3PT, England, UK
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Schwartz S, Herman M. Revisiting weight reduction and management in the diabetic patient: Novel therapies provide new strategies. Postgrad Med 2015; 127:480-93. [PMID: 25913393 DOI: 10.1080/00325481.2015.1043182] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022]
Abstract
Weight gain has been so synonymous with diabetes care that overweight/obesity is considered an intractable aspect of diabetes and its management. A healthy body mass index (BMI) is paramount, however, in preserving the cardiometabolic profile, slowing the course of the disease and extending the life expectancy of patients. It is also key to fostering a healthy and productive society at large. Two trends in care press us to challenge our assumptions about weight control in this population by reconsidering traditional approaches to the management of diabetes. First, new anti-diabetes drug classes have emerged that are more "weight-friendly" than previously available treatments and "gentler" on the faltering β cell. Second, novel anti-obesity agents are proving efficacious in patients with diabetes. This paper presents the composite of newer and older anti-obesity and anti-diabetic drugs. It makes recommendations for anti-diabetic regimens and processes of care that engender weight loss, or neutralize or minimize weight gain, while getting many patients to their glycated hemoglobin (HbA1c) goal. Anti-obesity agents that can be safely and effectively incorporated into these regimens for the patient needing supplemental support are reviewed in detail.
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Affiliation(s)
- Stanley Schwartz
- Main Line Health System, University of Pennsylvania, Philadelphia,, PA , USA
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14
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Raile K, Schober E, Konrad K, Thon A, Grulich-Henn J, Meissner T, Wölfle J, Scheuing N, Holl RW. Treatment of young patients with HNF1A mutations (HNF1A-MODY). Diabet Med 2015; 32:526-30. [PMID: 25483937 DOI: 10.1111/dme.12662] [Citation(s) in RCA: 31] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 12/02/2014] [Indexed: 12/15/2022]
Abstract
AIM Children and adolescents with a molecular diagnosis of HNF1A-MODY should be treated with oral sulfonylurea according to current International Society for Pediatric and Adolescent Diabetes (ISPAD) guidelines. METHODS We surveyed the German-Austrian DPV database of 50 043 people and included 114 patients with a confirmed molecular-genetic diagnosis of HNF1A mutation and diabetes onset at below age 18 years. We analysed hypoglycaemic episodes, metabolic control (HbA1c ) and other clinical variables according to treatment groups. RESULTS People with HNF1A-MODY were included and analysed according to treatment with insulin alone (n = 34), sulfonylurea (n = 30), meglitinides (n = 22) or lifestyle (n = 28). In those receiving any drug treatment (n = 86), severe hypoglycaemia did not occur with meglitinide and was highest (at 3.6 events per 100 patient-years) with insulin. HbA1c was highest with insulin treatment (insulin = 58 mmol/mol, 7.5%; sulfonylurea = 55 mmol/mol, 7.2%; meglitinides = 52 mmol/mol, 6.9%; P = 0.008), whereas weight (BMI SD score), serum lipids and blood pressure were not different. CONCLUSIONS Of note, 40% of people with HNF1A-MODY and medical treatment were receiving insulin alone and thus were not being treated in line with up-to-date International Society for Pediatric and Adolescent Diabetes/International Diabetes Federation guidelines, despite insulin treatment being associated with worse metabolic control and the risk of hypoglycaemia. The unlicensed use of oral drugs in patients below age 18 years and adherence by both doctors and patients to the initial insulin treatment might contribute to this finding.
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Affiliation(s)
- K Raile
- Experimental and Clinical Research Center, Charité, Berlin, Germany
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15
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Winkler G. [Sulfonylureas in today's blood glucose lowering therapy. New data on advantages and potential barriers of an "old" antidiabetic group]. Orv Hetil 2015; 156:511-5. [PMID: 25796278 DOI: 10.1556/oh.2015.30114] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/19/2022]
Abstract
Sulfonylurea compounds have been basic elements of antidiabetic treatment in type 2 diabetes for a long time. However, with the introduction of incretin type insulin secretagogues it is often arises, whether is still there a place for sulfonylureas in the today's therapy. To answer this question the author overviews general pharmaceutical characteristics of the sulfonylurea compounds as well as individual particularities of the second generation derivatives used at present in Hungary. The author details also the most important differences between incretin type drugs - first of all dipeptidyl peptidase-4 inhibitors - and sulfonylureas. On the basis of available data it can be concluded in accordance with the latest international guidelines, that sulfonylureas have still role in the blood glucose lowering therapy of type 2 diabetes, though they became somewhat pushed back among insulin secretagogue type drugs. If a sulfonylurea compound is the drug of choice, it is important to select the appropriate molecule (in case of normal renal function gliclazide or glimepiride). It is also important to re-educate the patient, as well as to apply the minimal dose providing the desired glycaemic effect.
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Affiliation(s)
- Gábor Winkler
- Fővárosi Szent János Kórház II. Belgyógyászat-Diabetológia Budapest Diós árok 1-3. 1125 Miskolci Egyetem, Egészségügyi Kar Elméleti Egészségtudományi Intézet Miskolc
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16
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Emami-Riedmaier A, Schaeffeler E, Nies AT, Mörike K, Schwab M. Stratified medicine for the use of antidiabetic medication in treatment of type II diabetes and cancer: where do we go from here? J Intern Med 2015; 277:235-247. [PMID: 25418285 DOI: 10.1111/joim.12330] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
At present, the global diabetes epidemic is affecting 347 million individuals, 90% of whom are diagnosed with type II diabetes mellitus (T2DM). T2DM is commonly treated with more than one type of therapy, including oral antidiabetic drugs (OADs) and agents used in the treatment of diabetic complications. Several pharmacological classes of OADs are currently available for the treatment of T2DM, of which insulin secretagogues (i.e. sulphonylureas and meglitinides), insulin sensitizers [thiazolidinediones (TZDs)] and biguanides are the most commonly prescribed. Although many of these OADs have been used for more than half a century in the treatment of T2DM, the pharmacogenomic characteristics of these compounds have only recently been investigated, primarily in retrospective studies. Recent advances in pharmacogenomics have led to the identification of polymorphisms that affect the expression and function of drug-metabolizing enzymes and drug transporters, as well as drug targets and receptors. These polymorphisms have been shown to affect the therapeutic response to and side effects associated with OADs. The aim of this review was to provide an up-to-date summary of some of the pharmacogenomic data obtained from studies of T2DM treatment, with a focus on polymorphisms in genes affecting pharmacokinetics, pharmacodynamics and treatment outcome of the most commonly prescribed OADs. In addition, the implications of pharmacogenomics in the use of the OAD metformin in cancer will be briefly discussed. Finally, we will focus on recent advances in novel 'omics' technologies and discuss how these might aid in the personalized management of T2DM.
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Affiliation(s)
- A Emami-Riedmaier
- Dr. Margarete Fischer-Bosch-Institute of Clinical Pharmacology, Stuttgart, Germany.,University of Tübingen, Tübingen, Germany
| | - E Schaeffeler
- Dr. Margarete Fischer-Bosch-Institute of Clinical Pharmacology, Stuttgart, Germany.,University of Tübingen, Tübingen, Germany
| | - A T Nies
- Dr. Margarete Fischer-Bosch-Institute of Clinical Pharmacology, Stuttgart, Germany.,University of Tübingen, Tübingen, Germany
| | - K Mörike
- Department of Clinical Pharmacology, University Hospital Tübingen, Tübingen, Germany
| | - M Schwab
- Dr. Margarete Fischer-Bosch-Institute of Clinical Pharmacology, Stuttgart, Germany.,Department of Clinical Pharmacology, University Hospital Tübingen, Tübingen, Germany
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17
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Brunetti A, Brunetti FS, Chiefari E. Pharmacogenetics of type 2 diabetes mellitus: An example of success in clinical and translational medicine. World J Transl Med 2014; 3:141-149. [DOI: 10.5528/wjtm.v3.i3.141] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/27/2014] [Revised: 09/25/2014] [Accepted: 11/03/2014] [Indexed: 02/05/2023] Open
Abstract
The pharmacological interventions currently available to control type 2 diabetes mellitus (T2DM) show a wide interindividual variability in drug response, emphasizing the importance of a personalized, more effective medical treatment for each individual patient. In this context, a growing interest has emerged in recent years and has focused on pharmacogenetics, a discipline aimed at understanding the variability in patients’ drug response, making it possible to predict which drug is best for each patient and at what doses. Recent pharmacological and clinical evidences indicate that genetic polymorphisms (or genetic variations) of certain genes can adversely affect drug response and therapeutic efficacy of oral hypoglycemic agents in patients with T2DM, through pharmacokinetic- and/or pharmacodynamic-based mechanisms that may reduce the therapeutic effects or increase toxicity. For example, genetic variants in genes encoding enzymes of the cytochrome P-450 superfamily, or proteins of the ATP-sensitive potassium channel on the beta-cell of the pancreas, are responsible for the interindividual variability of drug response to sulfonylureas in patients with T2DM. Instead, genetic variants in the genes that encode for the organic cation transporters of metformin have been related to changes in both pharmacodynamic and pharmacokinetic responses to metformin in metformin-treated patients. Thus, based on the individual’s genotype, the possibility, in these subjects, of a personalized therapy constitutes the main goal of pharmacogenetics, directly leading to the development of the right medicine for the right patient. Undoubtedly, this represents an integral part of the translational medicine network.
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18
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Laitinen R, Löbmann K, Grohganz H, Strachan C, Rades T. Amino acids as co-amorphous excipients for simvastatin and glibenclamide: physical properties and stability. Mol Pharm 2014; 11:2381-9. [PMID: 24852326 DOI: 10.1021/mp500107s] [Citation(s) in RCA: 77] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/24/2023]
Abstract
Co-amorphous drug mixtures with low-molecular-weight excipients have recently been shown to be a promising approach for stabilization of amorphous drugs and thus to be an alternative to the traditional amorphous solid dispersion approach using polymers. However, the previous studies are limited to a few drugs and amino acids. To facilitate the rational selection of amino acids, the practical importance of the amino acid coming from the biological target site of the drug (and associated intermolecular interactions) needs to be established. In the present study, the formation of co-amorphous systems using cryomilling and combinations of two poorly water-soluble drugs (simvastatin and glibenclamide) with the amino acids aspartic acid, lysine, serine, and threonine was investigated. Solid-state characterization with X-ray powder diffraction, differential scanning calorimetry, and Fourier-transform infrared spectroscopy revealed that the 1:1 molar combinations simvastatin-lysine, glibenclamide-serine, and glibenclamide-threonine and the 1:1:1 molar combination glibenclamide-serine-threonine formed co-amorphous mixtures. These were homogeneous single-phase blends with weak intermolecular interactions in the mixtures. Interestingly, a favorable effect by the excipients on the tautomerism of amorphous glibenclamide in the co-amorphous blends was seen, as the formation of the thermodynamically less stable imidic acid tautomer of glibenclamide was suppressed compared to that of the pure amorphous drug. Furthermore, the co-amorphous mixtures provided a physical stability advantage over the amorphous drugs alone.
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Affiliation(s)
- Riikka Laitinen
- School of Pharmacy, University of Eastern Finland , Kuopio FI-70211, Finland
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19
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Abstract
In addition to the common blood glucose lowering effect, sulfonylurea compounds are different in many aspects from each other. Based on earlier findings the second generation gliclazide has special advantages within this group. Although the number of experimental and clinical observations on gliclazide is continuously increasing, these novel findings are not in the focus anymore due to the appearance of new antidiabetics. This article reviews recent experimental (effect on receptors, the absence of Epac2 activation, antioxidant properties, possible incentive of factors participating in beta-cell differentiation) and pharmacogenomic data, and compares them with clinical observations obtained from gliclazide treatment (hypoglycemias, parameters of cardiovascular outcome). The data underline the advantages of gliclazide, the highly pancreas-selective nature, preservation of the ischemic precondition, favourable hemodynamic properties and potential reduction of the beta-cell loss as compared to other compounds of the group. However, gliclazide is not free from disadvantages characteristic to sulfonylureas in general (blood glucose independent insulin stimulation, beta-cell depletion). Comparing gliclazide with other derivatives of the group, the above data indicate individual benefits for the application when sulfonylurea compound is the drug of choice.
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Affiliation(s)
- Gábor Winkler
- Szent János Kórház II. Belgyógyászat-Diabetológia Budapest Diós árok 1-3. 1125 Miskolci Egyetem, Egészségügyi Kar Elméleti Egészségtudományi Intézet Miskolc
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20
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Abstract
For pediatric patients with hepatocyte nuclear factor-1A (HNF1A)-maturity-onset diabetes of the young (MODY 3), treatment with sulfonylureas is recommended. In adults with HNF1A-MODY, meglitinide analogues achieve lower postprandial glucose levels and pose a lower risk of delayed hypoglycemia compared with sulfonylureas. This therapy has not yet been reviewed in pediatric patients. We report on meglitinide analogue treatment in 3 adolescents with HNF1A-MODY. Case 1 (14-year-old girl) was diagnosed asymptomatically but had an hemoglobin A1c (HbA1c) level of 7.4%; her father had been recently diagnosed with HNF1A-MODY. With repaglinide, her HbA1c level decreased to 5.5%, with no hypoglycemic episodes. Case 2 (14-year-old boy) was diagnosed incidentally with glucosuria (HbA1c level: 7.0%) and was treated with insulin. After the HNF1A-MODY diagnosis, he was switched to glibenclamide. Due to several hypoglycemic episodes, treatment was changed to nateglinide and his HbA1c level decreased to 6.2% with no further hypoglycemic episodes. Case 3 (11-year-old girl) presented with polyuria and polydipsia (HbA1c level: 10.1%) and was initially treated with insulin. After the HNF1A-MODY diagnosis, treatment was changed to repaglinide. She was obese (BMI: 28.8 kg/m(2); z-score: +2.2), and glucose control with repaglinide alone was insufficient. Therefore, neutral protamine Hagedorn insulin (0.27 U/kg per day) was added. With this combination therapy, her HbA1c level decreased to 8.2%. The use of meglitinides in these 3 adolescent patients was well tolerated and effective. Furthermore, hypoglycemic episodes were rare compared with treatment with insulin or sulfonylureas. We therefore suggest considering meglitinides as the primary oral treatment option for adolescents suffering from HNF1A-MODY.
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Affiliation(s)
- Marianne Becker
- Department of Pediatric Endocrinology and Diabetology, Charité University Children's Hospital, Berlin, Germany; and
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21
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Becker ML, Pearson ER, Tkáč I. Pharmacogenetics of oral antidiabetic drugs. Int J Endocrinol 2013; 2013:686315. [PMID: 24324494 PMCID: PMC3845331 DOI: 10.1155/2013/686315] [Citation(s) in RCA: 32] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/15/2013] [Revised: 10/28/2013] [Accepted: 10/28/2013] [Indexed: 02/08/2023] Open
Abstract
Oral antidiabetic drugs (OADs) are used for more than a half-century in the treatment of type 2 diabetes. Only in the last five years, intensive research has been conducted in the pharmacogenetics of these drugs based mainly on the retrospective register studies, but only a handful of associations detected in these studies were replicated. The gene variants in CYP2C9, ABCC8/KCNJ11, and TCF7L2 were associated with the effect of sulfonylureas. CYP2C9 encodes sulfonylurea metabolizing cytochrome P450 isoenzyme 2C9, ABCC8 and KCNJ11 genes encode proteins constituting ATP-sensitive K(+) channel which is a therapeutic target for sulfonylureas, and TCF7L2 is a gene with the strongest association with type 2 diabetes. SLC22A1, SLC47A1, and ATM gene variants were repeatedly associated with the response to metformin. SLC22A1 and SLC47A1 encode metformin transporters OCT1 and MATE1, respectively. The function of a gene variant near ATM gene identified by a genome-wide association study is not elucidated so far. The first variant associated with the response to gliptins is a polymorphism in the proximity of CTRB1/2 gene which encodes chymotrypsinogen. Establishment of diabetes pharmacogenetics consortia and reduction in costs of genomics might lead to some significant clinical breakthroughs in this field in a near future.
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Affiliation(s)
- Matthijs L. Becker
- Department of Epidemiology, Erasmus MC, 3015 CE Rotterdam, The Netherlands
- Pharmacy Foundation of Haarlem Hospitals, 2035 RC Haarlem, The Netherlands
| | - Ewan R. Pearson
- Medical Research Institute, University of Dundee, Dundee DD1 9SY, UK
| | - Ivan Tkáč
- Department of Internal Medicine 4, Faculty of Medicine, P. J. Šafárik University, 041 80 Košice, Slovakia
- Department of Internal Medicine 4, L. Pasteur University Hospital, Rastislavova 43, 041 90 Košice, Slovakia
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22
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Javorský M, Babjaková E, Klimčáková L, Schroner Z, Židzik J, Štolfová M, Šalagovič J, Tkáč I. Association between TCF7L2 Genotype and Glycemic Control in Diabetic Patients Treated with Gliclazide. Int J Endocrinol 2013; 2013:374858. [PMID: 23509454 PMCID: PMC3590634 DOI: 10.1155/2013/374858] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/04/2012] [Accepted: 01/20/2013] [Indexed: 12/25/2022] Open
Abstract
Previous studies showed associations between variants in TCF7L2 gene and the therapeutic response to sulfonylureas. All sulfonylureas stimulate insulin secretion by the closure of ATP-sensitive potassium (KATP) channel. The aim of the present study was to compare TCF7L2 genotype specific effect of gliclazide binding to KATP channel A-site (Group 1) with sulfonylureas binding to AB-site (Group 2). A total of 101 patients were treated with sulfonylureas for 6 months as an add-on therapy to the previous metformin treatment. TCF7L2 rs7903146 C/T genotype was identified by real-time PCR with subsequent melting curve analysis. Analyses using the dominant genetic model showed significantly higher effect of gliclazide in the CC genotype group in comparison with combined CT + TT genotype group (1.32 ± 0.15% versus 0.73 ± 0.11%, P (adj) = 0.005). No significant difference in ΔHbA1c between the patients with CC genotype and the T-allele carriers was observed in Group 2. In the multivariate analysis, only the TCF7L2 genotype (P = 0.006) and the baseline HbA1c (P < 0.001) were significant predictors of ΔHbA1c. After introducing an interaction term between the TCF7L2 genotype and the sulfonylurea type into multivariate model, the interaction became a significant predictor (P = 0.023) of ΔHbA1c. The results indicate significantly higher difference in ΔHbA1c among the TCF7L2 genotypes in patients treated with gliclazide than in patients treated with glimepiride, glibenclamide, or glipizide.
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Affiliation(s)
- Martin Javorský
- Department of Internal Medicine 4, Faculty of Medicine, L. Pasteur University Hospital, P. J. Šafárik University in Košice, 041 90 Košice, Slovakia
| | - Eva Babjaková
- Department of Internal Medicine 4, Faculty of Medicine, L. Pasteur University Hospital, P. J. Šafárik University in Košice, 041 90 Košice, Slovakia
| | - Lucia Klimčáková
- Department of Medical Biology, Faculty of Medicine, P. J. Šafárik University in Košice, 040 66 Košice, Slovakia
| | - Zbynek Schroner
- Department of Internal Medicine 4, Faculty of Medicine, L. Pasteur University Hospital, P. J. Šafárik University in Košice, 041 90 Košice, Slovakia
| | - Jozef Židzik
- Department of Medical Biology, Faculty of Medicine, P. J. Šafárik University in Košice, 040 66 Košice, Slovakia
| | - Mária Štolfová
- Department of Internal Medicine 4, Faculty of Medicine, L. Pasteur University Hospital, P. J. Šafárik University in Košice, 041 90 Košice, Slovakia
| | - Ján Šalagovič
- Department of Medical Biology, Faculty of Medicine, P. J. Šafárik University in Košice, 040 66 Košice, Slovakia
| | - Ivan Tkáč
- Department of Internal Medicine 4, Faculty of Medicine, L. Pasteur University Hospital, P. J. Šafárik University in Košice, 041 90 Košice, Slovakia
- *Ivan Tkáč:
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Seino S. Cell signalling in insulin secretion: the molecular targets of ATP, cAMP and sulfonylurea. Diabetologia 2012; 55:2096-108. [PMID: 22555472 DOI: 10.1007/s00125-012-2562-9] [Citation(s) in RCA: 83] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/20/2012] [Accepted: 03/09/2012] [Indexed: 12/25/2022]
Abstract
Clarification of the molecular mechanisms of insulin secretion is crucial for understanding the pathogenesis and pathophysiology of diabetes and for development of novel therapeutic strategies for the disease. Insulin secretion is regulated by various intracellular signals generated by nutrients and hormonal and neural inputs. In addition, a variety of glucose-lowering drugs including sulfonylureas, glinide-derivatives, and incretin-related drugs such as dipeptidyl peptidase IV (DPP-4) inhibitors and glucagon-like peptide 1 (GLP-1) receptor agonists are used for glycaemic control by targeting beta cell signalling for improved insulin secretion. There has been a remarkable increase in our understanding of the basis of beta cell signalling over the past two decades following the application of molecular biology, gene technology, electrophysiology and bioimaging to beta cell research. This review discusses cell signalling in insulin secretion, focusing on the molecular targets of ATP, cAMP and sulfonylurea, an essential metabolic signal in glucose-induced insulin secretion (GIIS), a critical signal in the potentiation of GIIS, and the commonly used glucose-lowering drug, respectively.
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Affiliation(s)
- S Seino
- Division of Diabetes and Endocrinology, Department of Internal Medicine, Kobe University Graduate School of Medicine, Kobe, 650-0017, Japan.
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Pharmacogenomic analysis of ATP-sensitive potassium channels coexpressing the common type 2 diabetes risk variants E23K and S1369A. Pharmacogenet Genomics 2012; 22:206-14. [PMID: 22209866 DOI: 10.1097/fpc.0b013e32835001e7] [Citation(s) in RCA: 30] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/01/2023]
Abstract
OBJECTIVES The common ATP-sensitive potassium (KATP) channel variants E23K and S1369A, found in the KCNJ11 and ABCC8 genes, respectively, form a haplotype that is associated with an increased risk for type 2 diabetes. Our previous studies showed that KATP channel inhibition by the A-site sulfonylurea gliclazide was increased in the K23/A1369 haplotype. Therefore, we studied the pharmacogenomics of seven clinically used sulfonylureas and glinides to determine their structure-activity relationships in KATP channels containing either the E23/S1369 nonrisk or K23/A1369 risk haplotypes. RESEARCH DESIGN AND METHODS The patch-clamp technique was used to determine sulfonylurea and glinide inhibition of recombinant human KATP channels containing either the E23/S1369 or the K23/A1369 haplotype. RESULTS KATP channels containing the K23/A1369 risk haplotype were significantly less sensitive to inhibition by tolbutamide, chlorpropamide, and glimepiride (IC50 values for K23/A1369 vs. E23/S1369=1.15 vs. 0.71 μmol/l; 4.19 vs. 3.04 μmol/l; 4.38 vs. 2.41 nmol/l, respectively). In contrast, KATP channels containing the K23/A1369 haplotype were significantly more sensitive to inhibition by mitiglinide (IC50=9.73 vs. 28.19 nmol/l for K23/A1369 vs. E23/S1369) and gliclazide. Nateglinide, glipizide, and glibenclamide showed similar inhibitory profiles in KATP channels containing either haplotype. CONCLUSION Our results demonstrate that the ring-fused pyrrole moiety in several A-site drugs likely underlies the observed inhibitory potency of these drugs on KATP channels containing the K23/A1369 risk haplotype. It may therefore be possible to tailor existing therapy or design novel drugs that display an increased efficacy in type 2 diabetes patients homozygous for these common KATP channel haplotypes.
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Abdelmoneim AS, Hasenbank SE, Seubert JM, Brocks DR, Light PE, Simpson SH. Variations in tissue selectivity amongst insulin secretagogues: a systematic review. Diabetes Obes Metab 2012; 14:130-8. [PMID: 21923736 DOI: 10.1111/j.1463-1326.2011.01496.x] [Citation(s) in RCA: 65] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/25/2022]
Abstract
AIM Insulin secretagogues promote insulin release by binding to sulfonylurea receptors on pancreatic β-cells (SUR1). However, these drugs also bind to receptor isoforms on cardiac myocytes (SUR2A) and vascular smooth muscle (SUR2B). Binding to SUR2A/SUR2B may inhibit ischaemic preconditioning, an endogenous protective mechanism enabling cardiac tissue to survive periods of ischaemia. This study was designed to identify insulin secretagogues that selectively bind to SUR1 when given at therapeutic doses. METHODS Using accepted systematic review methods, three electronic databases were searched from inception to 13 June 2011. Original studies measuring the half-maximal inhibitory concentration (IC(50)) for an insulin secretagogue on K(ATP) channels using standard electrophysiological techniques were included. Steady-state concentrations (C(SS)) were estimated from the usual oral dose and clearance values for each drug. RESULTS Data were extracted from 27 studies meeting all inclusion criteria. IC(50) values for SUR1 were below those for SUR2A/SUR2B for all insulin secretagogues and addition of C(SS) values identified three distinct patterns. The C(SS) for gliclazide, glipizide, mitiglinide and nateglinide lie between IC(50) values for SUR1 and SUR2A/SUR2B, suggesting that these drugs bind selectively to pancreatic receptors. The C(SS) for glimepiride and glyburide (glibenclamide) was above IC(50) values for all three isoforms, suggesting these drugs are non-selective. Tolbutamide and repaglinide may have partial pancreatic receptor selectivity because IC(50) values for SUR1 and SUR2A/SUR2B overlapped somewhat, with the C(SS) in the midst of these values. CONCLUSIONS Insulin secretagogues display different tissue selectivity characteristics at therapeutic doses. This may translate into different levels of cardiovascular risk.
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MESH Headings
- ATP-Binding Cassette Transporters/drug effects
- ATP-Binding Cassette Transporters/metabolism
- Animals
- Carbamates/adverse effects
- Cardiovascular Diseases/chemically induced
- Cardiovascular Diseases/metabolism
- Cardiovascular Diseases/physiopathology
- Cricetinae
- Cyclohexanes/adverse effects
- Diabetes Mellitus, Type 2/drug therapy
- Diabetes Mellitus, Type 2/metabolism
- Gliclazide/adverse effects
- Glipizide/adverse effects
- Glyburide/adverse effects
- Humans
- Hypoglycemic Agents/adverse effects
- Hypoglycemic Agents/pharmacology
- Ischemic Preconditioning, Myocardial
- Isoindoles/adverse effects
- Mice
- Muscle, Smooth, Vascular/drug effects
- Muscle, Smooth, Vascular/metabolism
- Muscle, Smooth, Vascular/physiopathology
- Myocytes, Cardiac/drug effects
- Myocytes, Cardiac/metabolism
- Nateglinide
- Phenylalanine/adverse effects
- Phenylalanine/analogs & derivatives
- Piperidines/adverse effects
- Potassium Channels, Inwardly Rectifying/drug effects
- Potassium Channels, Inwardly Rectifying/metabolism
- Rats
- Receptors, Drug/drug effects
- Receptors, Drug/metabolism
- Risk Factors
- Sulfonylurea Compounds/adverse effects
- Sulfonylurea Receptors
- Tolbutamide/adverse effects
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Affiliation(s)
- A S Abdelmoneim
- Faculty of Pharmacy & Pharmaceutical Sciences, 3126 Dentistry/Pharmacy Centre, University of Alberta, Edmonton, Alberta, Canada
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26
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Schmid D, Stolzlechner M, Sorgner A, Bentele C, Assinger A, Chiba P, Moeslinger T. An abundant, truncated human sulfonylurea receptor 1 splice variant has prodiabetic properties and impairs sulfonylurea action. Cell Mol Life Sci 2012; 69:129-48. [PMID: 21671119 PMCID: PMC11114697 DOI: 10.1007/s00018-011-0739-x] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2010] [Revised: 05/20/2011] [Accepted: 05/23/2011] [Indexed: 12/20/2022]
Abstract
An alternatively spliced form of human sulfonylurea receptor (SUR) 1 mRNA lacking exon 2 (SUR1Δ2) has been identified. The omission of exon 2 caused a frame shift and an immediate stop codon in exon 3 leading to translation of a 5.6-kDa peptide that comprises the N-terminal extracellular domain and the first transmembrane helix of SUR1. Based on a weak first splice acceptor site in the human SUR1 gene (ABCC8), RT-PCR revealed a concurrent expression of SUR1Δ2 and SUR1. The SUR1Δ2/(SUR1 + SUR1Δ2) mRNA ratio differed between tissues, and was lowest in pancreas (46%), highest in heart (88%) and negatively correlated with alternative splice factor/splicing factor 2 (ASF/SF2) expression. In COS-7 cells triple transfected with SUR1Δ2/SUR1/Kir6.2, the SUR1Δ2 peptide co-immunoprecipitated with Kir6.2, thereby displacing two of four SUR1 subunits on the cell surface. The ATP sensitivity of these hybrid ATP-sensitive potassium channels (K(ATP)) channels was reduced by about sixfold, as shown with single-channel recordings. RINm5f rat insulinoma cells, which genuinely express SUR1 but not SUR1Δ2, exhibited a strongly increased K(ATP) channel current upon transfection with SUR1Δ2. This led to inhibition of glucose-induced depolarization, calcium flux, insulin release and glibenclamide action. A non-mutagenic SNP on nucleotide position 333 (Pro69Pro) added another exonic splicing enhancer sequence detected by ASF/SF2, reduced relative abundance of SUR1Δ2 and slightly protected from non-insulin dependent diabetes in homozygotic individuals. Thus, SUR1Δ2 represents an endogenous K(ATP)-channel modulator with prodiabetic properties in islet cells. Its predominance in heart may explain why high-affinity sulfonylurea receptors are not found in human cardiac tissue.
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MESH Headings
- ATP-Binding Cassette Transporters/genetics
- ATP-Binding Cassette Transporters/metabolism
- Alternative Splicing/physiology
- Animals
- COS Cells
- Calcium/metabolism
- Chlorocebus aethiops
- Diabetes Mellitus, Type 2/genetics
- Diabetes Mellitus, Type 2/metabolism
- Diabetes Mellitus, Type 2/physiopathology
- Exons/physiology
- Glyburide/pharmacology
- Humans
- Hypoglycemic Agents/pharmacology
- Insulin/metabolism
- Islets of Langerhans/metabolism
- KATP Channels/drug effects
- KATP Channels/metabolism
- Myocardium/metabolism
- Organ Specificity/genetics
- Pancreas/metabolism
- Polymorphism, Single Nucleotide
- Potassium Channels, Inwardly Rectifying/genetics
- Potassium Channels, Inwardly Rectifying/metabolism
- RNA, Messenger/genetics
- RNA, Messenger/metabolism
- Rats
- Receptors, Drug/genetics
- Receptors, Drug/metabolism
- Species Specificity
- Sulfonylurea Receptors
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Affiliation(s)
- Diethart Schmid
- Institute of Physiology, Center for Physiology and Pharmacology, Medical University of Vienna, Vienna, Austria.
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27
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Seino S, Takahashi H, Takahashi T, Shibasaki T. Treating diabetes today: a matter of selectivity of sulphonylureas. Diabetes Obes Metab 2012; 14 Suppl 1:9-13. [PMID: 22118705 DOI: 10.1111/j.1463-1326.2011.01507.x] [Citation(s) in RCA: 46] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
It is well known that sulphonylureas (SUs), commonly used in the treatment of type 2 diabetes mellitus, stimulate insulin secretion by closing ATP-sensitive K(+) (K(ATP) ) channels in pancreatic β-cells by binding to the SU receptor SUR1. SUs are now known also to activate cAMP sensor Epac2 (cAMP-GEFII) to Rap1 signalling, which promotes insulin granule exocytosis. For SUs to exert their full effects in insulin secretion, they are required to activate Epac2 as well as to inhibit the β-cell K(ATP) channels. As Epac2 is also necessary for potentiation of glucose-induced insulin secretion by cAMP-increasing agents, such as incretin, Epac2 is a target of both cAMP and SUs. The distinct effects of various SUs appear to be because of their different actions on Epac2/Rap1 signalling as well as K(ATP) channels. Differently from other SUs, gliclazide is unique in that it is specific for β-cell K(ATP) channel and does not activate Epac2.
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Affiliation(s)
- S Seino
- Division of Diabetes and Endocrinology, Department of Internal Medicine, Kobe University Graduate School of Medicine, Chuo-ku, Kobe, Japan.
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28
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Lang V, Youssef N, Light PE. The molecular genetics of sulfonylurea receptors in the pathogenesis and treatment of insulin secretory disorders and type 2 diabetes. Curr Diab Rep 2011; 11:543-51. [PMID: 21968738 DOI: 10.1007/s11892-011-0233-8] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
Sulfonylurea receptors (SURs) form an integral part of the ATP-sensitive potassium (K(ATP)) channel complex that is present in most excitable cell types. K(ATP) channels couple cellular metabolism to electrical activity and provide a wide range of cellular functions including stimulus secretion coupling in pancreatic β cells. K(ATP) channels are composed of SURs and inward rectifier potassium channel (Kir6.x) subunits encoded by the ABCC8/9 and KCNJ8/11 genes, respectively. Recent advances in the genetics, molecular biology, and pharmacology of SURs have led to an increased understanding of these channels in the etiology and treatment of rare genetic insulin secretory disorders. Furthermore, common genetic variants in these genes are associated with an increased risk for type 2 diabetes. In this review we summarize the molecular biology, pharmacology, and physiology of SURs and K(ATP) channels, highlighting recent advances in their genetics and understanding of rare insulin secretory disorders and susceptibility to type 2 diabetes.
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Affiliation(s)
- Veronica Lang
- Department of Pharmacology, Alberta Diabetes Institute and Cardiovascular Research Centre, University of Alberta, Edmonton, Alberta T6G 2E1, Canada
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29
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Winkler M, Kühner P, Russ U, Ortiz D, Bryan J, Quast U. Role of the amino-terminal transmembrane domain of sulfonylurea receptor SUR2B for coupling to KIR6.2, ligand binding, and oligomerization. Naunyn Schmiedebergs Arch Pharmacol 2011; 385:287-98. [DOI: 10.1007/s00210-011-0708-9] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2011] [Accepted: 10/24/2011] [Indexed: 01/11/2023]
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30
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Kühner P, Prager R, Stephan D, Russ U, Winkler M, Ortiz D, Bryan J, Quast U. Importance of the Kir6.2 N-terminus for the interaction of glibenclamide and repaglinide with the pancreatic KATP channel. Naunyn Schmiedebergs Arch Pharmacol 2011; 385:299-311. [DOI: 10.1007/s00210-011-0709-8] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2011] [Accepted: 10/24/2011] [Indexed: 11/28/2022]
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31
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Sato R, Watanabe H, Genma R, Takeuchi M, Maekawa M, Nakamura H. ABCC8 polymorphism (Ser1369Ala): influence on severe hypoglycemia due to sulfonylureas. Pharmacogenomics 2011; 11:1743-50. [PMID: 21142918 DOI: 10.2217/pgs.10.135] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022] Open
Abstract
AIMS Sulfonylureas are categorized according to their binding sites of the ATP-sensitive K+ channel (K(ATP) channel) complex in pancreatic β-cells. The binding sites are classified as A, B and A + B site (both A and B sites), respectively. The Ser1369Ala variant in the sulfonylurea receptor gene ABCC8 which encodes a subunit of the K(ATP) channel complex has been demonstrated to be associated with the hypoglycemic effect of gliclazide, which binds to the A site. However, the hypoglycemic effect of the Ser1369Ala variant on treatment with A + B binding site sulfonylureas, such as glimepiride or glibenclamide, is still uncertain. MATERIALS & METHODS In a case-control study, 32 patients with Type 2 diabetes admitted to hospital with severe hypoglycemia and 125 consecutive Type 2 diabetic outpatients without severe hypoglycemia were enrolled. We determined the genotypes of the ABCC8 polymorphism (Ser1369Ala) in the patients with or without severe hypoglycemia. All of the patients were taking glimepiride or glibenclamide. RESULTS In the patients treated with glimepiride or glibenclamide, we found no significant differences in the distribution of the Ser1369Ala genotype between patients with or without severe hypoglycemia (p = 0.26). Moreover, the Ala1369 minor allele tended to be less frequent in the hypoglycemic group (31 vs 43%; OR: 1.65; 95% CI: 0.92-2.96; p = 0.09). CONCLUSION Our findings suggest that the Ser1369Ala variant is not a major predictive factor of severe hypoglycemia due to glimepiride or glibenclamide, both of which bind to the A + B site. It is likely that severe hypoglycemia due to A + B binding site sulfonylureas will be mediated by other factors, and not the Ala1369 minor allele.
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Affiliation(s)
- Ryosuke Sato
- Department of Endocrinology & Metabolism, Hamamatsu University School of Medicine, Hamamatsu, Japan.
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32
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Lang V, Light PE. The molecular mechanisms and pharmacotherapy of ATP-sensitive potassium channel gene mutations underlying neonatal diabetes. Pharmgenomics Pers Med 2010; 3:145-61. [PMID: 23226049 PMCID: PMC3513215 DOI: 10.2147/pgpm.s6969] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2010] [Indexed: 12/14/2022] Open
Abstract
Neonatal diabetes mellitus (NDM) is a monogenic disorder caused by mutations in genes involved in regulation of insulin secretion from pancreatic β-cells. Mutations in the KCNJ11 and ABCC8 genes, encoding the adenosine triphosphate (ATP)-sensitive potassium (K(ATP)) channel Kir6.2 and SUR1 subunits, respectively, are found in ∼50% of NDM patients. In the pancreatic β-cell, K(ATP) channel activity couples glucose metabolism to insulin secretion via cellular excitability and mutations in either KCNJ11 or ABCC8 genes alter K(ATP) channel activity, leading to faulty insulin secretion. Inactivation mutations decrease K(ATP) channel activity and stimulate excessive insulin secretion, leading to hyperinsulinism of infancy. In direct contrast, activation mutations increase K(ATP) channel activity, resulting in impaired insulin secretion, NDM, and in severe cases, developmental delay and epilepsy. Many NDM patients with KCNJ11 and ABCC8 mutations can be successfully treated with sulfonylureas (SUs) that inhibit the K(ATP) channel, thus replacing the need for daily insulin injections. There is also strong evidence indicating that SU therapy ameliorates some of the neurological defects observed in patients with more severe forms of NDM. This review focuses on the molecular and cellular mechanisms of mutations in the K(ATP) channel that underlie NDM. SU pharmacogenomics is also discussed with respect to evaluating whether patients with certain K(ATP) channel activation mutations can be successfully switched to SU therapy.
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Affiliation(s)
- Veronica Lang
- Department of Pharmacology and Alberta Diabetes Institute, Faculty of Medicine and Dentistry, School of Molecular and Systems Medicine, University of Alberta, Edmonton, Alberta, Canada
| | - Peter E Light
- Department of Pharmacology and Alberta Diabetes Institute, Faculty of Medicine and Dentistry, School of Molecular and Systems Medicine, University of Alberta, Edmonton, Alberta, Canada
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33
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Amann T, Schell S, Kühner P, Winkler M, Schwanstecher M, Russ U, Quast U. Substitution of the Walker A lysine by arginine in the nucleotide-binding domains of sulphonylurea receptor SUR2B: effects on ligand binding and channel activity. Naunyn Schmiedebergs Arch Pharmacol 2010; 381:507-16. [PMID: 20352196 DOI: 10.1007/s00210-010-0510-0] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2009] [Accepted: 02/28/2010] [Indexed: 10/19/2022]
Abstract
Sulphonylurea receptors (SURs) serve as regulatory subunits of ATP-sensitive K(+) channels. SURs are members of the ATP-binding cassette (ABC) protein superfamily and contain two conserved nucleotide-binding domains (NBDs) which bind and hydrolyse MgATP; in addition, they carry the binding sites for the sulphonylureas like glibenclamide (GBC) which close the channel and for the K(ATP) channel openers such as P1075. Here we have exchanged the conserved Lys in the Walker A motif by Arg in both NBDs of SUR2B, the regulatory subunit of the vascular K(ATP) channel. Then the effect of the mutation on the ATPase-dependent binding of GBC and P1075 to SUR2B and on the activity of the recombinant vascular (Kir6.1/SUR2B) channel was assessed. Surprisingly, in the absence of MgATP, the mutation weakened binding of P1075 and the extent of allosteric inhibition of GBC binding by P1075. The mutation abolished most, but not all, of the MgATP effects on the binding of GBC and P1075 and prevented nucleotide-induced activation of the channel which relies on SUR reaching the posthydrolytic (MgADP-bound) state; the mutant channel was, however, opened by P1075 at higher concentrations. The data provide evidence that mutant SUR2B binds MgATP but that the posthydrolytic state is insufficiently populated. This suggests that the mutation locks SUR2B in an MgATP-binding prehydrolytic-like state; binding of P1075 may induce a posthydrolytic-like conformation to open the channel.
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Affiliation(s)
- Tobias Amann
- Department of Pharmacology and Experimental Therapy, Institute of Experimental and Clinical Pharmacology and Toxicology, Eberhard-Karls-University Hospitals and Clinics, University of Tübingen, Wilhelmstr. 56, 72074, Tübingen, Germany
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34
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Hamming KS, Soliman D, Matemisz LC, Niazi O, Lang Y, Gloyn AL, Light PE. Coexpression of the type 2 diabetes susceptibility gene variants KCNJ11 E23K and ABCC8 S1369A alter the ATP and sulfonylurea sensitivities of the ATP-sensitive K(+) channel. Diabetes 2009; 58:2419-24. [PMID: 19587354 PMCID: PMC2750221 DOI: 10.2337/db09-0143] [Citation(s) in RCA: 91] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
OBJECTIVE In the pancreatic beta-cell, ATP-sensitive K(+) (K(ATP)) channels couple metabolism with excitability and consist of Kir6.2 and SUR1 subunits encoded by KCNJ11 and ABCC8, respectively. Sulfonylureas, which inhibit the K(ATP) channel, are used to treat type 2 diabetes. Rare activating mutations cause neonatal diabetes, whereas the common variants, E23K in KCNJ11 and S1369A in ABCC8, are in strong linkage disequilibrium, constituting a haplotype that predisposes to type 2 diabetes. To date it has not been possible to establish which of these represents the etiological variant, and functional studies are inconsistent. Furthermore, there have been no studies of the S1369A variant or the combined effect of the two on K(ATP) channel function. RESEARCH DESIGN AND METHODS The patch-clamp technique was used to study the nucleotide sensitivity and sulfonylurea inhibition of recombinant human K(ATP) channels containing either the K23/A1369 or E23/S1369 variants. RESULTS ATP sensitivity of the K(ATP) channel was decreased in the K23/A1369 variant (half-maximal inhibitory concentration [IC(50)] = 8.0 vs. 2.5 mumol/l for the E23/S1369 variant), although there was no difference in ADP sensitivity. The K23/A1369 variant also displayed increased inhibition by gliclazide, an A-site sulfonylurea drug (IC(50) = 52.7 vs. 188.7 nmol/l for the E23/S1369 variant), but not by glibenclamide (AB site) or repaglinide (B site). CONCLUSIONS Our findings indicate that the common K23/A1369 variant K(ATP) channel displays decreased ATP inhibition that may contribute to the observed increased risk for type 2 diabetes. Moreover, the increased sensitivity of the K23/A1369 variant to the A-site sulfonylurea drug gliclazide may provide a pharmacogenomic therapeutic approach for patients with type 2 diabetes who are homozygous for both risk alleles.
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Affiliation(s)
- Kevin S.C. Hamming
- Department of Pharmacology, Alberta Diabetes Institute, University of Alberta, Edmonton, Alberta, Canada
| | - Daniel Soliman
- Department of Pharmacology, Alberta Diabetes Institute, University of Alberta, Edmonton, Alberta, Canada
| | - Laura C. Matemisz
- Department of Pharmacology, Alberta Diabetes Institute, University of Alberta, Edmonton, Alberta, Canada
| | - Omid Niazi
- Department of Pharmacology, Alberta Diabetes Institute, University of Alberta, Edmonton, Alberta, Canada
| | - Yiqiao Lang
- Department of Pharmacology, Alberta Diabetes Institute, University of Alberta, Edmonton, Alberta, Canada
| | - Anna L. Gloyn
- Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Oxford, U.K
| | - Peter E. Light
- Department of Pharmacology, Alberta Diabetes Institute, University of Alberta, Edmonton, Alberta, Canada
- Corresponding author: Peter E. Light,
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35
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Winkler M, Lutz R, Russ U, Quast U, Bryan J. Analysis of two KCNJ11 neonatal diabetes mutations, V59G and V59A, and the analogous KCNJ8 I60G substitution: differences between the channel subtypes formed with SUR1. J Biol Chem 2009; 284:6752-62. [PMID: 19139106 PMCID: PMC2652280 DOI: 10.1074/jbc.m805435200] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2008] [Revised: 12/09/2008] [Indexed: 11/06/2022] Open
Abstract
beta-Cell-type K(ATP) channels are octamers assembled from Kir6.2/KCNJ11 and SUR1/ABCC8. Adenine nucleotides play a major role in their regulation. Nucleotide binding to Kir6.2 inhibits channel activity, whereas ATP binding/hydrolysis on sulfonylurea receptor 1 (SUR1) opposes inhibition. Segments of the Kir6.2 N terminus are important for open-to-closed transitions, form part of the Kir ATP, sulfonylurea, and phosphoinositide binding sites, and interact with L0, an SUR cytoplasmic loop. Inputs from these elements link to the pore via the interfacial helix, which forms an elbow with the outer pore helix. Mutations that destabilize the interfacial helix increase channel activity, reduce sensitivity to inhibitory ATP and channel inhibitors, glibenclamide and repaglinide, and cause neonatal diabetes. We compared Kir6.x/SUR1 channels carrying the V59G substitution, a cause of the developmental delay, epilepsy, and neonatal diabetes syndrome, with a V59A substitution and the equivalent I60G mutation in the related Kir6.1 subunit from vascular smooth muscle. The substituted channels have increased P(O) values, decreased sensitivity to inhibitors, and impaired stimulation by phosphoinositides but retain sensitivity to Ba(2+)-block. The V59G and V59A channels are either not, or poorly, stimulated by phosphoinositides, respectively. Inhibition by sequestrating phosphatidylinositol 4,5-bisphosphate with neomycin and polylysine is reduced in V59A, and abolished in V59G channels. Stimulation by SUR1 is intact, and increasing the concentration of inhibitory ATP restores the sensitivity of Val-59-substituted channels to glibenclamide. The I60G channels, strongly dependent on SUR stimulation, remain sensitive to sulfonylureas. The results suggest the interfacial helix dynamically links inhibitory inputs from the Kir N terminus to the gate and that sulfonylureas stabilize an inhibitory configuration.
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MESH Headings
- ATP-Binding Cassette Transporters/genetics
- ATP-Binding Cassette Transporters/metabolism
- Amino Acid Substitution
- Cell Line
- Developmental Disabilities/genetics
- Developmental Disabilities/metabolism
- Diabetes Mellitus/genetics
- Diabetes Mellitus/metabolism
- Epilepsy/genetics
- Epilepsy/metabolism
- Genetic Diseases, Inborn/genetics
- Genetic Diseases, Inborn/metabolism
- Humans
- Infant, Newborn
- Ion Channel Gating/drug effects
- Ion Channel Gating/genetics
- KATP Channels
- Muscle, Smooth, Vascular/metabolism
- Mutation, Missense
- Myocytes, Smooth Muscle/metabolism
- Potassium Channel Blockers/pharmacology
- Potassium Channels, Inwardly Rectifying/genetics
- Potassium Channels, Inwardly Rectifying/metabolism
- Receptors, Drug/genetics
- Receptors, Drug/metabolism
- Sulfonylurea Receptors
- Syndrome
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Affiliation(s)
- Marcus Winkler
- Department of Pharmacology and Toxicology, Medical Faculty, University of Tübingen, Wilhelmstrasse 56, Tübingen D-72074, Germany
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36
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Russ U, Kühner P, Prager R, Stephan D, Bryan J, Quast U. Incomplete dissociation of glibenclamide from wild-type and mutant pancreatic K ATP channels limits their recovery from inhibition. Br J Pharmacol 2009; 156:354-61. [PMID: 19154434 DOI: 10.1111/j.1476-5381.2008.00005.x] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/25/2022] Open
Abstract
BACKGROUND AND PURPOSE The antidiabetic sulphonylurea, glibenclamide, acts by inhibiting the pancreatic ATP-sensitive K(+) (K(ATP)) channel, a tetradimeric complex of K(IR)6.2 and sulphonylurea receptor 1 (K(IR)6.2/SUR1)(4). At room temperature, recovery of channel activity following washout of glibenclamide is very slow and cannot be measured. This study investigates the relation between the recovery of channel activity from glibenclamide inhibition and the dissociation rate of [(3)H]-glibenclamide from the channel at 37 degrees C. EXPERIMENTAL APPROACH K(IR)6.2, K(IR)6.2DeltaN5 or K(IR)6.2DeltaN10 (the latter lacking amino-terminal residues 2-5 or 2-10 respectively) were coexpressed with SUR1 in HEK cells. Dissociation of [(3)H]-glibenclamide from the channel and recovery of channel activity from glibenclamide inhibition were determined at 37 degrees C. KEY RESULTS The dissociation kinetics of [(3)H]-glibenclamide from the wild-type channel followed an exponential decay with a dissociation half-time, t(1/2)(D) = 14 min; however, only limited and slow recovery of channel activity was observed. t(1/2)(D) for K(IR)6.2DeltaN5/SUR1 channels was 5.3 min and recovery of channel activity exhibited a sluggish sigmoidal time course with a half-time, t(1/2)(R) = 12 min. t(1/2)(D) for the DeltaN10 channel was 2.3 min; recovery kinetics were again sigmoidal with t(1/2)(R) approximately 4 min. CONCLUSIONS AND IMPLICATIONS The dissociation of glibenclamide from the truncated channels is the rate-limiting step of channel recovery. The sigmoidal recovery kinetics are in quantitative agreement with a model where glibenclamide must dissociate from all four (or at least three) sites before the channel reopens. It is argued that these conclusions hold also for the wild-type (pancreatic) K(ATP) channel.
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Affiliation(s)
- U Russ
- Department of Pharmacology and Toxicology, Medical Faculty, University of Tübingen, Wilhelmstrasse 56, Tübingen, Germany
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