|
1
|
Lin ZM, Gao HY, Shi SH, Li YT. Mizagliflozin ameliorates diabetes induced kidney injury by inhibitor inhibit inflammation and oxidative stress. World J Diabetes 2025; 16:92711. [PMID: 39817219 PMCID: PMC11718448 DOI: 10.4239/wjd.v16.i1.92711] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/05/2024] [Revised: 04/26/2024] [Accepted: 10/08/2024] [Indexed: 11/29/2024] Open
Abstract
BACKGROUND Mizagliflozin (MIZ) is a specific inhibitor of sodium-glucose cotransport protein 1 (SGLT1) originally developed as a medication for diabetes. AIM To explore the impact of MIZ on diabetic nephropathy (DN). METHODS Diabetic mice were created using db/db mice. They were administered either a low dose (0.5 mg/kg) or a high dose (1.0 mg/kg) of the SGLT1 inhibitor MIZ via stomach gavage for 8 weeks. Subsequently, mesangial cells (MCs) were isolated and subjected to high glucose conditions in culture to assess the effects of MIZ on DN. RESULTS The results showed that low doses of MIZ significantly reduced albuminuria to a level comparable to that achieved with high doses in db/db mice. High doses of MIZ led to a substantial increase in body weight in mice, along with decreased blood glucose levels and food intake. Moreover, the intervention with high-dose MIZ notably decreased the expression of extracellular matrix genes, such as collagen type 1 alpha 1 mRNA levels. While the expression of SGLT1 increased after exposure to high glucose, it decreased following treatment with MIZ. Furthermore, MIZ intervention was more effective in improving lactate dehydrogenase levels in MCs induced by high glucose compared to canagliflozin. MIZ also significantly elevated levels of antioxidant enzymes superoxide dismutase, catalase, and glutathione, while reducing malondialdehyde levels. CONCLUSION These findings indicate that MIZ can ameliorate DN by inhibiting SGLT1, inflammation, and oxidative stress.
Collapse
Affiliation(s)
- Zhi-Min Lin
- Department of Nephrology, The Second Affiliated Hospital of Fujian Medical University, Quanzhou 362000, Fujian Province, China
| | - Han-Yuan Gao
- Department of Nephrology, The Second Affiliated Hospital of Fujian Medical University, Quanzhou 362000, Fujian Province, China
| | - Shu-Han Shi
- Department of Nephrology, The Second Affiliated Hospital of Fujian Medical University, Quanzhou 362000, Fujian Province, China
| | - Yue-Ting Li
- Department of Nephrology, The Second Affiliated Hospital of Fujian Medical University, Quanzhou 362000, Fujian Province, China
| |
Collapse
|
|
2
|
Du J, Shen M, Chen J, Yan H, Xu Z, Yang X, Yang B, Luo P, Ding K, Hu Y, He Q. The impact of solute carrier proteins on disrupting substance regulation in metabolic disorders: insights and clinical applications. Front Pharmacol 2025; 15:1510080. [PMID: 39850557 PMCID: PMC11754210 DOI: 10.3389/fphar.2024.1510080] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2024] [Accepted: 12/20/2024] [Indexed: 01/25/2025] Open
Abstract
Carbohydrates, lipids, bile acids, various inorganic salt ions and organic acids are the main nutrients or indispensable components of the human body. Dysregulation in the processes of absorption, transport, metabolism, and excretion of these metabolites can lead to the onset of severe metabolic disorders, such as type 2 diabetes, non-alcoholic fatty liver disease, gout and hyperbilirubinemia. As the second largest membrane receptor supergroup, several major families in the solute carrier (SLC) supergroup have been found to play key roles in the transport of substances such as carbohydrates, lipids, urate, bile acids, monocarboxylates and zinc ions. Based on common metabolic dysregulation and related metabolic substances, we explored the relationship between several major families of SLC supergroup and metabolic diseases, providing examples of drugs targeting SLC proteins that have been approved or are currently in clinical/preclinical research as well as SLC-related diagnostic techniques that are in clinical use or under investigation. By highlighting these connections, we aim to provide insights that may contribute to the development of improved treatment strategies and targeted therapies for metabolic disorders.
Collapse
Affiliation(s)
- Jiangxia Du
- Center for Medical Research and Innovation in Digestive System Tumors, Ministry of Education, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
| | - Minhui Shen
- Center for Drug Safety Evaluation and Research of Zhejiang University, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, Zhejiang, China
| | - Jiajia Chen
- Center for Drug Safety Evaluation and Research of Zhejiang University, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, Zhejiang, China
| | - Hao Yan
- Center for Drug Safety Evaluation and Research of Zhejiang University, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, Zhejiang, China
| | - Zhifei Xu
- Center for Drug Safety Evaluation and Research of Zhejiang University, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, Zhejiang, China
| | - Xiaochun Yang
- Center for Drug Safety Evaluation and Research of Zhejiang University, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, Zhejiang, China
| | - Bo Yang
- Institute of Pharmacology and Toxicology, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, Zhejiang, China
- School of Medicine, Hangzhou City University, Hangzhou, Zhejiang, China
| | - Peihua Luo
- Center for Drug Safety Evaluation and Research of Zhejiang University, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, Zhejiang, China
- Department of Pharmaceutical and Translational Toxicology, Innovation Institute for Artificial Intelligence in Medicine of Zhejiang University, Hangzhou, Zhejiang, China
| | - Kefeng Ding
- Center for Medical Research and Innovation in Digestive System Tumors, Ministry of Education, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
| | - Yuhuai Hu
- Yuhong Pharmaceutical Technology Co., Ltd., Hangzhou, Zhejiang, China
| | - Qiaojun He
- Center for Medical Research and Innovation in Digestive System Tumors, Ministry of Education, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
- Center for Drug Safety Evaluation and Research of Zhejiang University, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, Zhejiang, China
- School of Medicine, Hangzhou City University, Hangzhou, Zhejiang, China
- Department of Pharmaceutical and Translational Toxicology, Innovation Institute for Artificial Intelligence in Medicine of Zhejiang University, Hangzhou, Zhejiang, China
| |
Collapse
|
|
3
|
Sánchez-Muñoz E, Requena-Ibáñez JA, Badimón JJ. Dual SGLT1 and SGLT2 inhibition: more than the sum of its parts. REVISTA ESPANOLA DE CARDIOLOGIA (ENGLISH ED.) 2024; 77:510-514. [PMID: 38521442 DOI: 10.1016/j.rec.2024.01.011] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/09/2023] [Accepted: 01/04/2024] [Indexed: 03/25/2024]
Affiliation(s)
- Enrique Sánchez-Muñoz
- Servicio de Cardiología, Complejo Asistencial Universitario de León, León, Spain; Atherothrombosis Research Unit, Mount Sinai Fuster Heart Hospital, Icahn School of Medicine at Mount Sinai, Nueva York, Estados Unidos.
| | - Juan Antonio Requena-Ibáñez
- Atherothrombosis Research Unit, Mount Sinai Fuster Heart Hospital, Icahn School of Medicine at Mount Sinai, Nueva York, Estados Unidos
| | - Juan José Badimón
- Atherothrombosis Research Unit, Mount Sinai Fuster Heart Hospital, Icahn School of Medicine at Mount Sinai, Nueva York, Estados Unidos
| |
Collapse
|
|
4
|
Forester BR, Zhang R, Schuhler B, Brostek A, Gonzalez-Vicente A, Garvin JL. Knocking Out Sodium Glucose-Linked Transporter 5 Prevents Fructose-Induced Renal Oxidative Stress and Salt-Sensitive Hypertension. Hypertension 2024; 81:1296-1307. [PMID: 38545789 PMCID: PMC11096007 DOI: 10.1161/hypertensionaha.123.22535] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2023] [Accepted: 03/05/2024] [Indexed: 05/18/2024]
Abstract
BACKGROUND A fructose high-salt (FHS) diet increases systolic blood pressure and Ang II (angiotensin II)-stimulated proximal tubule (PT) superoxide (O2-) production. These increases are prevented by scavenging O2- or an Ang II type 1 receptor antagonist. SGLT4 (sodium glucose-linked cotransporters 4) and SGLT5 are implicated in PT fructose reabsorption, but their roles in fructose-induced hypertension are unclear. We hypothesized that PT fructose reabsorption by SGLT5 initiates a genetic program enhancing Ang II-stimulated oxidative stress in males and females, thereby causing fructose-induced salt-sensitive hypertension. METHODS We measured systolic blood pressure in male and female Sprague-Dawley (wild type [WT]), SGLT4 knockout (-/-), and SGLT5-/- rats. Then, we measured basal and Ang II-stimulated (37 nmol/L) O2- production by PTs and conducted gene coexpression network analysis. RESULTS In male WT and female WT rats, FHS increased systolic blood pressure by 15±3 (n=7; P<0.0027) and 17±4 mm Hg (n=9; P<0.0037), respectively. Male and female SGLT4-/- had similar increases. Systolic blood pressure was unchanged by FHS in male and female SGLT5-/-. In male WT and female WT fed FHS, Ang II stimulated O2- production by 14±5 (n=6; P<0.0493) and 8±3 relative light units/µg protein/s (n=7; P<0.0218), respectively. The responses of SGTL4-/- were similar. Ang II did not stimulate O2- production in tubules from SGLT5-/-. Five gene coexpression modules were correlated with FHS. These correlations were completely blunted in SGLT5-/- and partially blunted by chronically scavenging O2- with tempol. CONCLUSIONS SGLT5-mediated PT fructose reabsorption is required for FHS to augment Ang II-stimulated proximal nephron O2- production, and increases in PT oxidative stress likely contribute to FHS-induced hypertension.
Collapse
Affiliation(s)
- Beau R. Forester
- Department of Physiology and Biophysics, Case Western Reserve University School of Medicine, Cleveland, Ohio
| | - Ronghao Zhang
- Department of Physiology and Biophysics, Case Western Reserve University School of Medicine, Cleveland, Ohio
- Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology & Emory University, Atlanta. Georgia
- Department of Cell Biology, Emory University School of Medicine, Atlanta, Georgia
| | - Brett Schuhler
- Department of Physiology and Biophysics, Case Western Reserve University School of Medicine, Cleveland, Ohio
| | - Autumn Brostek
- Department of Physiology and Biophysics, Case Western Reserve University School of Medicine, Cleveland, Ohio
| | - Agustin Gonzalez-Vicente
- Department of Physiology and Biophysics, Case Western Reserve University School of Medicine, Cleveland, Ohio
- Department of Kidney Medicine, Glickman Urological & Kidney Institute, Cleveland Clinic Cleveland, Ohio
| | - Jeffrey L. Garvin
- Department of Physiology and Biophysics, Case Western Reserve University School of Medicine, Cleveland, Ohio
| |
Collapse
|
|
5
|
Zhao J, Sun H, Wang C, Shang D. Breast cancer therapy: from the perspective of glucose metabolism and glycosylation. Mol Biol Rep 2024; 51:546. [PMID: 38642246 DOI: 10.1007/s11033-024-09466-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2024] [Accepted: 03/22/2024] [Indexed: 04/22/2024]
Abstract
Breast cancer is a leading cause of mortality and the most prevalent form of malignant tumor among women worldwide. Breast cancer cells exhibit an elevated glycolysis and altered glucose metabolism. Moreover, these cells display abnormal glycosylation patterns, influencing invasion, proliferation, metastasis, and drug resistance. Consequently, targeting glycolysis and mitigating abnormal glycosylation represent key therapeutic strategies for breast cancer. This review underscores the importance of protein glycosylation and glucose metabolism alterations in breast cancer. The current research efforts in developing effective interventions targeting glycolysis and glycosylation are further discussed.
Collapse
Affiliation(s)
- Jiaqi Zhao
- Department of Pharmacy, School of Chemistry and Chemical Engineering, Liaoning Normal University, Dalian, 116029, China
| | - Haiting Sun
- Department of Pharmacy, School of Chemistry and Chemical Engineering, Liaoning Normal University, Dalian, 116029, China
| | - Che Wang
- Department of Pharmacy, School of Chemistry and Chemical Engineering, Liaoning Normal University, Dalian, 116029, China.
- Liaoning Provincial Key Laboratory of Biotechnology and Drug Discovery, School of Life Science, Liaoning Normal University, Dalian, 116081, China.
| | - Dejing Shang
- Liaoning Provincial Key Laboratory of Biotechnology and Drug Discovery, School of Life Science, Liaoning Normal University, Dalian, 116081, China.
| |
Collapse
|
|
6
|
Huang L, Cao B, Geng Y, Zhou X, Yang Y, Ma T, Lin H, Huang Z, Zhuo L, Li J. A randomized double-blind phase Ib clinical trial of SY-009 in patients with type 2 diabetes mellitus. Eur J Pharm Sci 2024; 192:106644. [PMID: 37981049 DOI: 10.1016/j.ejps.2023.106644] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2022] [Revised: 10/18/2023] [Accepted: 11/16/2023] [Indexed: 11/21/2023]
Abstract
INTRODUCTION SY-009 produces a hypoglycemic effect via inhibiting sodium/glucose cotransporter 1 (SGLT1) in type 2 diabetes mellitus (T2DM) patients. This randomized, double-blind, placebo-controlled, and multiple-dose escalation clinical trial aimed to evaluate the pharmacokinetic and pharmacodynamical characteristics as well as the safety and tolerability of SY-009 in T2DM patients. METHOD Fifty T2DM patients were randomized into experimental and placebo groups, and hospitalized for 9 days managed with a unified diet and rest management. Subjects were given SY-009 or placebo from day 1 to day 7 at different frequencies and dosages. Single dose cohort was defined as the first dose on day 1 and multiple dose cohort included all the dose from day 1 to 7. Blood samples were collected for pharmacokinetic analysis. Mixed meal tolerance tests were performed. Blood samples were collected to determine glucose, C-peptide, insulin, glucagon-like peptide-1 (GLP-1), and gastric inhibitory polypeptide (GIP). RESULTS PK parameters were not obtained because blood SY-009 concentrations were below the limit of quantitation in all subjects. SY-009 decreased the postprandial glucose. Blood glucose was controlled within 4 hours after taking the drug. Short-term administration of SY-009 (7 days) had no significant effects on fasting glucose but reduced the secretion of C-peptide, insulin, and GIP and increased GLP-1 secretion. The most common adverse event was gastrointestinal disorder manifesting abdominal pain, diarrhea, and bloating. CONCLUSION Plasma exposure of SY-009 and its metabolites was fairly low in T2DM patients at doses of 1.0-4.0 mg. SY-009 reduced postprandial glucose, C-peptide, and insulin levels, showing relative safety and tolerability in the dose range of 1.0-4.0 mg. TRIALS REGISTRATION ClinicalTrials.gov Identifier: NCT04345107.
Collapse
Affiliation(s)
- Lei Huang
- Phase I Clinical Trials Unit, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, 210008, China
| | - Bei Cao
- Phase I Clinical Trials Unit, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, 210008, China
| | - Yan Geng
- Phase I Clinical Trials Unit, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, 210008, China
| | - Xiaoli Zhou
- Suzhou Yabao Pharmaceutical R&D Co., Ltd., Suzhou 215000, China
| | - Yuanxun Yang
- Phase I Clinical Trials Unit, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, 210008, China
| | - Tingting Ma
- Phase I Clinical Trials Unit, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, 210008, China
| | - Hui Lin
- Phase I Clinical Trials Unit, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, 210008, China
| | - Zhijiang Huang
- Suzhou Yabao Pharmaceutical R&D Co., Ltd., Suzhou 215000, China
| | - Lang Zhuo
- Suzhou Yabao Pharmaceutical R&D Co., Ltd., Suzhou 215000, China.
| | - Juan Li
- Phase I Clinical Trials Unit, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, 210008, China.
| |
Collapse
|
|
7
|
Kishida K, Iida T, Yamada T, Toyoda Y. Intestinal absorption of D-fructose isomers, D-allulose, D-sorbose and D-tagatose, via glucose transporter type 5 (GLUT5) but not sodium-dependent glucose cotransporter 1 (SGLT1) in rats. Br J Nutr 2023; 130:1852-1858. [PMID: 38713062 DOI: 10.1017/s0007114523001113] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/08/2024]
Abstract
D-allulose, D-sorbose and D-tagatose are D-fructose isomers that are called rare sugars. These rare sugars have been studied intensively in terms of biological production and food application as well as physiological effects. There are limited papers with regard to the transporters mediating the intestinal absorption of these rare sugars. We examined whether these rare sugars are absorbed via sodium-dependent glucose cotransporter 1 (SGLT1) as well as via GLUT type 5 (GLUT5) using rats. High-fructose diet fed rats, which express more intestinal GLUT5, exhibited significantly higher peripheral concentrations, Cmax and AUC0–180 min when D-allulose, D-sorbose and D-tagatose were orally administrated. KGA-2727, a selective SGLT1 inhibitor, did not affect the peripheral and portal vein concentrations and pharmacokinetic parameters of these rare sugars. The results suggest that D-allulose, D-sorbose and D-tagatose are likely transported via GLUT5 but not SGLT1 in rat small intestine.
Collapse
Affiliation(s)
- Kunihiro Kishida
- Department of Science and Technology on Food Safety, Kindai University, 930 Nishimitani, Kinokawa, Wakayama649-6493, Japan
| | - Tetsuo Iida
- Research and Development, Matsutani Chemical Industry Company, Limited, 5-3 Kita-Itami, Itami, Hyogo664-8508, Japan
| | - Takako Yamada
- Research and Development, Matsutani Chemical Industry Company, Limited, 5-3 Kita-Itami, Itami, Hyogo664-8508, Japan
| | - Yukiyasu Toyoda
- Department of Pathobiochemistry, Faculty of Pharmacy, Meijo University, 150 Yagotoyama, Tempaku-ku, Nagoya, Aichi468-8503, Japan
| |
Collapse
|
|
8
|
Azizogli AR, Vitti MR, Mishra R, Osorno L, Heffernan C, Kumar VA. Comparison of SGLT1, SGLT2, and Dual Inhibitor biological activity in treating Type 2 Diabetes Mellitus. ADVANCED THERAPEUTICS 2023; 6:2300143. [PMID: 38223846 PMCID: PMC10783160 DOI: 10.1002/adtp.202300143] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2023] [Indexed: 01/16/2024]
Abstract
Diabetes Mellitus Type 2 (T2D) is an emerging health burden in the USand worldwide, impacting approximately 15% of Americans. Current front-line therapeutics for T2D patients include sulfonylureas that act to reduce A1C and/or fasting blood glucose levels, or Metformin that antagonizes the action of glucagon to reduce hepatic glucose production. Next generation glucomodulatory therapeutics target members of the high-affinity glucose transporter Sodium-Glucose-Linked-Transporter (SGLT) family. SGLT1 is primarily expressed in intestinal epithelium, whose inhibition reduces dietary glucose uptake, whilst SGLT2 is highly expressed in kidney - regulating glucose reabsorption. A number of SGLT2 inhibitors are FDA approved whilst SGLT1 and dual SGLT1 & 2 inhibitor are currently in clinical trials. Here, we discuss and compare SGLT2, SGLT1, and dual inhibitors' biochemical mechanism and physiological effects.
Collapse
Affiliation(s)
- Abdul-Rahman Azizogli
- Department of Biological Sciences, New Jersey Institute of Technology, Newark, NJ, 07102
| | - Michael R Vitti
- University of Virginia School of Medicine, Charlottesville, VA, 22903
| | - Richa Mishra
- Department of Biomedical Engineering, New Jersey Institute of Technology, Newark, NJ, 07102
| | - Laura Osorno
- Department of Biomedical Engineering, New Jersey Institute of Technology, Newark, NJ, 07102
| | - Corey Heffernan
- Department of Biomedical Engineering, New Jersey Institute of Technology, Newark, NJ, 07102
| | - Vivek A Kumar
- Department of Biomedical Engineering, New Jersey Institute of Technology, Newark, NJ, 07102
- Department of Biological Sciences, New Jersey Institute of Technology, Newark, NJ, 07102
- Department of Chemical and Materials Engineering, New Jersey Institute of Technology, Newark, NJ, 07102
- Department of Endodontics, Rutgers School of Dental Medicine, Newark, NJ, 07103
| |
Collapse
|
|
9
|
Haider S, Mushtaq M, Nur-E-Alam M, Ahmed A, Ul-Haq Z. Identification of novel small molecule inhibitors for solute carrier SGLT1; a computational exploration. J Biomol Struct Dyn 2023; 42:12537-12547. [PMID: 37855364 DOI: 10.1080/07391102.2023.2270708] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2023] [Accepted: 10/08/2023] [Indexed: 10/20/2023]
Abstract
Diabetes results in substantial disabilities, diminished quality of life, and mortality that imposes a huge economic burden on societies and governments worldwide. Despite the absence of specific oral therapies at present, there exists an urgent requirement to develop a novel drug for the treatment of diabetes mellitus. The membrane protein sodium glucose co-transporters (SGLT1) present a captivating therapeutic target for diabetes, given its pivotal role in facilitating glucose absorption in the small intestine, offering immense promise for potential therapeutic intervention. In this connection, the present study is aimed at identifying potential inhibitors of SGLT1 from a small molecule database, including compounds from both natural as well as synthetic origins. A comprehensive approach was employed, by integrating homology modeling, ligand-based pharmacophore modeling, virtual screening, and molecular docking simulation. The process resulted in the identification of 16 new compounds, featuring similar attributes as observed for the documented actives. In a systematic screening procedure, five potential virtual hits were selected for simulation studies followed by subsequent binding free energy calculations, providing deeper insight into the time-dependent behavior of protein-ligand complexes in a dynamic state. In conclusion, our findings demonstrated that the identified compounds, particularly compounds 81 and 91, exhibit enhanced stability and favorable binding affinities with the target protein, marking them promising candidates for further investigations.Communicated by Ramaswamy H. Sarma.
Collapse
Affiliation(s)
- Sajjad Haider
- H. E. J. Research Institute of Chemistry, International Center for Chemical and Biological Sciences, University of Karachi, Karachi, Pakistan
| | - Mamona Mushtaq
- Dr. Panjwani Center for Molecular Medicine and Drug Research, International Center for Chemical and Biological Sciences, University of Karachi, Karachi, Pakistan
| | - Mohammad Nur-E-Alam
- Department of Pharmacognosy, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia
| | - Aftab Ahmed
- Chapman University School of pharmacy, Irvine, CA, USA
| | - Zaheer Ul-Haq
- Dr. Panjwani Center for Molecular Medicine and Drug Research, International Center for Chemical and Biological Sciences, University of Karachi, Karachi, Pakistan
| |
Collapse
|
|
10
|
Tsunokake S, Iwabuchi E, Miki Y, Kanai A, Onodera Y, Sasano H, Ishida T, Suzuki T. SGLT1 as an adverse prognostic factor in invasive ductal carcinoma of the breast. Breast Cancer Res Treat 2023; 201:499-513. [PMID: 37439959 DOI: 10.1007/s10549-023-07024-9] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2023] [Accepted: 06/26/2023] [Indexed: 07/14/2023]
Abstract
PURPOSE Sodium/glucose cotransporter (SGLT) 1 and 2 expression in carcinoma cells was recently examined, but their association with the clinicopathological factors of the patients and their biological effects on breast carcinoma cells have remained remain virtually unknown. Therefore, in this study, we explored the expression status of SGLT1 and SGLT2 in breast cancer patients and examined the effects of SGLT1 inhibitors on breast carcinoma cells in vitro. METHODS SGLT1 and SGLT2 were immunolocalized and we first correlated the findings with clinicopathological factors of the patients. We then administered mizagliflozin and KGA-2727, SGLT1 specific inhibitors to MCF-7 and MDA-MB-468 breast carcinoma cell lines, and their growth-inhibitory effects were examined. Protein arrays were then used to further explore their effects on the growth factors. RESULTS The SGLT1 high group had significantly worse clinical outcome including both overall survival and disease-free survival than low group. SGLT2 status was not significantly correlated with clinical outcome of the patients. Both mizagliflozin and KGA-2727 inhibited the growth of breast cancer cell lines. Of particular interest, mizagliflozin inhibited the proliferation of MCF-7 cells, even under very low glucose conditions. Mizagliflozin downregulated vascular endothelial growth factor receptor 2 phosphorylation. CONCLUSION High SGLT1 expression turned out as an adverse clinical prognostic factor in breast cancer patient. This is the first study demonstrating that SGLT1 inhibitors suppressed breast carcinoma cell proliferation. These results indicated that SGLT1 inhibitors could be used as therapeutic agents for breast cancer patients with aggressive biological behaviors.
Collapse
Affiliation(s)
- Satoko Tsunokake
- Department of Breast and Endocrine Surgical Oncology, Tohoku University Graduate School of Medicine, Sendai, Miyagi, Japan
| | - Erina Iwabuchi
- Department of Pathology and Histotechnology, Tohoku University Graduate School of Medicine, Sendai, Miyagi, Japan.
| | - Yasuhiro Miki
- Department of Anatomic Pathology, Tohoku University Graduate School of Medicine, Sendai, Miyagi, Japan
| | - Ayako Kanai
- Department of Breast Surgery, Hachinohe City Hospital, Hachinohe, Aomori, Japan
| | - Yoshiaki Onodera
- Department of Anatomic Pathology, Tohoku University Graduate School of Medicine, Sendai, Miyagi, Japan
| | - Hironobu Sasano
- Department of Anatomic Pathology, Tohoku University Graduate School of Medicine, Sendai, Miyagi, Japan
| | - Takanori Ishida
- Department of Breast and Endocrine Surgical Oncology, Tohoku University Graduate School of Medicine, Sendai, Miyagi, Japan
| | - Takashi Suzuki
- Department of Pathology and Histotechnology, Tohoku University Graduate School of Medicine, Sendai, Miyagi, Japan
- Department of Anatomic Pathology, Tohoku University Graduate School of Medicine, Sendai, Miyagi, Japan
| |
Collapse
|
|
11
|
Impact of Lycium barbarum polysaccharide on the expression of glucagon-like peptide 1 in vitro and in vivo. Int J Biol Macromol 2022; 224:908-918. [DOI: 10.1016/j.ijbiomac.2022.10.176] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2022] [Revised: 10/12/2022] [Accepted: 10/20/2022] [Indexed: 11/05/2022]
|
|
12
|
Maccari R, Ottanà R. Sodium-Glucose Cotransporter Inhibitors as Antidiabetic Drugs: Current Development and Future Perspectives. J Med Chem 2022; 65:10848-10881. [PMID: 35924548 PMCID: PMC9937539 DOI: 10.1021/acs.jmedchem.2c00867] [Citation(s) in RCA: 20] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/28/2022]
Abstract
Sodium-glucose cotransporter 2 (SGLT-2) inhibitors (gliflozins) represent the most recently approved class of oral antidiabetic drugs. SGLT-2 overexpression in diabetic patients contributes significantly to hyperglycemia and related complications. Therefore, SGLT-2 became a highly interesting therapeutic target, culminating in the approval for clinical use of dapagliflozin and analogues in the past decade. Gliflozins improve glycemic control through a novel insulin-independent mechanism of action and, moreover, exhibit significant cardiorenal protective effects in both diabetic and nondiabetic subjects. Therefore, gliflozins have received increasing attention, prompting extensive structure-activity relationship studies and optimization approaches. The discovery that intestinal SGLT-1 inhibition can provide a novel opportunity to control hyperglycemia, through a multifactorial mechanism, recently encouraged the design of low adsorbable inhibitors selectively directed to the intestinal SGLT-1 subtype as well as of dual SGLT-1/SGLT-2 inhibitors, representing a compelling strategy to identify new antidiabetic drug candidates.
Collapse
Affiliation(s)
- Rosanna Maccari
- Department of Chemical, Biological, Pharmaceutical and Environmental Sciences, University of Messina, Viale F. Stagno D'Alcontres, 31, 98166 Messina, Italy
| | - Rosaria Ottanà
- Department of Chemical, Biological, Pharmaceutical and Environmental Sciences, University of Messina, Viale F. Stagno D'Alcontres, 31, 98166 Messina, Italy
| |
Collapse
|
|
13
|
Li Y, Feng R, Yu X, Li L, Liu Y, Zhang R, Chen X, Zhao Y, Liu Z. SLC35E2 promoter mutation as a prognostic marker of esophageal squamous cell carcinoma. Life Sci 2022; 296:120447. [PMID: 35247439 DOI: 10.1016/j.lfs.2022.120447] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2021] [Revised: 01/29/2022] [Accepted: 02/26/2022] [Indexed: 12/24/2022]
Abstract
AIMS Esophageal squamous cell carcinoma (ESCC) is one of the deadliest digestive tract cancer with poor prognosis. In our previous comprehensive genomics study, we identified that hotspot mutations in the solute carrier family 35 member E2 (SLC35E2) promoter region was significantly associated with worse prognosis in patients with ESCC. However, the biological function and molecular mechanism of SLC35E2 remains unclear. This study was to investigate the malignant function and mechanism of SLC35E2 in ESCC. MAIN METHODS Western blotting and qRT-PCR were used to assess the expression of SLC35E2 in ESCC cell lines. Luciferase assay and chromatin immunoprecipitation (ChIP) assay were used to assess the transcriptional inhibition of KLF4. Incucyte cell proliferation assay, colony formation assay and subcutaneous tumor formation in nude mice were used to assess the malignant function of SLC35E2. KEY FINDINGS SLC35E2 can promote ESCC cell proliferation in vitro and in vivo. Krüppel-like factor 4 (KLF4), a transcriptional repressor in ESCC, binds to the SLC35E2 promoter and represses the expression of SLC35E2. The transcriptional suppression of KLF4 can be blocked by the mutation at -118 site of the SLC35E2 promoter. Besides, the accumulation of SLC35E2 expression contributes to the malignant phenotype of ESCC. SIGNIFICANCE These results indicate that SLC35E2 may be used as a biomarker for prognosis as well as a therapeutic target for patients with ESCC.
Collapse
Affiliation(s)
- Yang Li
- State Key Laboratory of Molecular Oncology, National Cancer Center, National Clinical Research Center for Cancer, Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China
| | - Riyue Feng
- State Key Laboratory of Molecular Oncology, National Cancer Center, National Clinical Research Center for Cancer, Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China
| | - Xiao Yu
- State Key Laboratory of Molecular Oncology, National Cancer Center, National Clinical Research Center for Cancer, Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China
| | - Lei Li
- State Key Laboratory of Molecular Oncology, National Cancer Center, National Clinical Research Center for Cancer, Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China
| | - Yuhao Liu
- State Key Laboratory of Molecular Oncology, National Cancer Center, National Clinical Research Center for Cancer, Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China
| | - Ruixiang Zhang
- State Key Laboratory of Molecular Oncology, Department of Thoracic Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China
| | - Xiankai Chen
- State Key Laboratory of Molecular Oncology, Department of Thoracic Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China
| | - Yahui Zhao
- State Key Laboratory of Molecular Oncology, National Cancer Center, National Clinical Research Center for Cancer, Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China
| | - Zhihua Liu
- State Key Laboratory of Molecular Oncology, National Cancer Center, National Clinical Research Center for Cancer, Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China.
| |
Collapse
|
|
14
|
Zhu H, Cai H, Wang X, Chen T, Zhen C, Zhang Z, Ruan X, Li G. Sodium-glucose co-transporter 1 (SGLT1) differentially regulates gluconeogenesis and GLP-1 receptor (GLP-1R) expression in different diabetic rats: a preliminary validation of the hypothesis of "SGLT1 bridge" as an indication for "surgical diabetes". ANNALS OF TRANSLATIONAL MEDICINE 2022; 10:481. [PMID: 35571394 PMCID: PMC9096370 DOI: 10.21037/atm-22-1769] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/14/2022] [Accepted: 04/20/2022] [Indexed: 11/24/2022]
Abstract
BACKGROUND Sodium-glucose co-transporter 1 (SGLT1) may play a synergistic role in gluconeogenesis (GNG) and glucagon-like peptide-1 (GLP-1) expression. We proposed the hypothesis of a "SGLT1 bridge" as an indication for "surgical diabetes" that was preliminary validated in the present study. METHODS We selected nonobese diabetic Goto-Kakizaki (GK) rats and Zuker diabetic fat (ZDF) rats to represent advanced and early diabetes, respectively. Based on glucose gavage with or without SGLT1 inhibitor phlorizin, the rats were divided into 4 groups: Gk-Glu, GK-P, ZDF-Glu, and ZDF-P. The expressions of SGLT1, GLP-1 receptor (GLP-1R), glucose-6 phosphatase (G6Pase), and phosphoenolpyruvate carboxykinase-1 (Pck1) were determined by immunohistochemistry (IHC) or quantitative reverse transcription polymerase chain reaction (RT-qPCR), and the effects of phlorizin were analyzed. RESULTS Glucose tolerance was worse in GK rats and the homeostasis model assessment-insulin resistance (HOMA-IR) was higher in ZDF rats, indicating different pathophysiological conditions between the different diabetic rats. GK rats showed higher activity of duodenal SGLT1 (P=0.022) and jejunal SGLT1 mRNA expression (P=0.000) and lower SGLT1 mRNA expression in the liver (P=0.000) and pancreas (P=0.000). Phlorizin effectively inhibited the activity of duodenal SGLT1 in both GK rats (P=0.000) and ZDF rats (P=0.000). In ZDF rats, the expression of GLP-1R mRNA was downregulated in the jejunum (P=0.001) and upregulated in the pancreas (P=0.021) by phlorizin, but there were no regulatory effects on GLP-1R mRNA in the jejunum and pancreas of GK rats. As for the regulatory effects on GNG, phlorizin upregulated Pck1 mRNA in the duodenum (P=0.000) and the jejunum (P=0.038), whereas it downregulated hepatic G6Pase mRNA in ZDF rats (P=0.005) and Pck1 mRNA expression in GK rats (P=0.001), suggesting that SGLT1 inhibitor may have upregulated intestinal GNG in ZDF rats and downregulated hepatic GNG in both ZDF and GK rats. CONCLUSIONS SGLT1 showed synergistic regulatory effects on the entero-insular axis (EIA) and the gut-brain-liver axis (GBLA), preliminarily validating the hypothesis of a "SGLT1 bridge". The distinct expression of SGLT1 and its differentially regulatory effects on diabetic rats with different pathophysiological conditions may provide probable potential indications involved in the "Surgical Diabetes" that is supposed as the inclusion for diabetic surgery.
Collapse
Affiliation(s)
- Hengliang Zhu
- Department of General Surgery & Guangdong Provincial Key Laboratory of Precision Medicine for Gastrointestinal Tumor, Nanfang Hospital, Southern Medical University, Guangzhou, China
- Department of General Surgery, Shenzhen University General Hospital & Shenzhen University Clinical Medical Academy, Shenzhen University, Shenzhen, China
| | - Huajie Cai
- Department of Gastrointestinal Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Xiaokun Wang
- Department of Gastrointestinal & Hernia Surgery, Ganzhou People’s Hospital, Ganzhou, China
| | - Tao Chen
- Department of General Surgery & Guangdong Provincial Key Laboratory of Precision Medicine for Gastrointestinal Tumor, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Chaohui Zhen
- Department of General Surgery, Shenzhen University General Hospital & Shenzhen University Clinical Medical Academy, Shenzhen University, Shenzhen, China
| | - Zhenzhan Zhang
- Department of General Surgery & Guangdong Provincial Key Laboratory of Precision Medicine for Gastrointestinal Tumor, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Xiaojiao Ruan
- Department of Gastrointestinal Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Guoxin Li
- Department of General Surgery & Guangdong Provincial Key Laboratory of Precision Medicine for Gastrointestinal Tumor, Nanfang Hospital, Southern Medical University, Guangzhou, China
| |
Collapse
|
|
15
|
Lin S, Larrue C, Scheidegger NK, Seong BKA, Dharia NV, Kuljanin M, Wechsler CS, Kugener G, Robichaud AL, Conway AS, Mashaka T, Mouche S, Adane B, Ryan JA, Mancias JD, Younger ST, Piccioni F, Lee LH, Wunderlich M, Letai A, Tamburini J, Stegmaier K. An In Vivo CRISPR Screening Platform for Prioritizing Therapeutic Targets in AML. Cancer Discov 2022; 12:432-449. [PMID: 34531254 PMCID: PMC8831447 DOI: 10.1158/2159-8290.cd-20-1851] [Citation(s) in RCA: 46] [Impact Index Per Article: 15.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2020] [Revised: 07/26/2021] [Accepted: 09/13/2021] [Indexed: 02/02/2023]
Abstract
CRISPR-Cas9-based genetic screens have successfully identified cell type-dependent liabilities in cancer, including acute myeloid leukemia (AML), a devastating hematologic malignancy with poor overall survival. Because most of these screens have been performed in vitro using established cell lines, evaluating the physiologic relevance of these targets is critical. We have established a CRISPR screening approach using orthotopic xenograft models to validate and prioritize AML-enriched dependencies in vivo, including in CRISPR-competent AML patient-derived xenograft (PDX) models tractable for genome editing. Our integrated pipeline has revealed several targets with translational value, including SLC5A3 as a metabolic vulnerability for AML addicted to exogenous myo-inositol and MARCH5 as a critical guardian to prevent apoptosis in AML. MARCH5 repression enhanced the efficacy of BCL2 inhibitors such as venetoclax, further highlighting the clinical potential of targeting MARCH5 in AML. Our study provides a valuable strategy for discovery and prioritization of new candidate AML therapeutic targets. SIGNIFICANCE: There is an unmet need to improve the clinical outcome of AML. We developed an integrated in vivo screening approach to prioritize and validate AML dependencies with high translational potential. We identified SLC5A3 as a metabolic vulnerability and MARCH5 as a critical apoptosis regulator in AML, both of which represent novel therapeutic opportunities.This article is highlighted in the In This Issue feature, p. 275.
Collapse
Affiliation(s)
- Shan Lin
- Department of Pediatric Oncology, Dana-Farber Cancer Institute and Boston Children's Hospital, Boston, Massachusetts.,The Broad Institute of MIT and Harvard, Cambridge, Massachusetts
| | - Clément Larrue
- Translational Research Centre in Onco-hematology, Faculty of Medicine, University of Geneva, Geneva, Switzerland
| | - Nastassja K. Scheidegger
- Department of Pediatric Oncology, Dana-Farber Cancer Institute and Boston Children's Hospital, Boston, Massachusetts.,The Broad Institute of MIT and Harvard, Cambridge, Massachusetts
| | - Bo Kyung A. Seong
- Department of Pediatric Oncology, Dana-Farber Cancer Institute and Boston Children's Hospital, Boston, Massachusetts.,The Broad Institute of MIT and Harvard, Cambridge, Massachusetts
| | - Neekesh V. Dharia
- Department of Pediatric Oncology, Dana-Farber Cancer Institute and Boston Children's Hospital, Boston, Massachusetts.,The Broad Institute of MIT and Harvard, Cambridge, Massachusetts
| | - Miljan Kuljanin
- Department of Radiation Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts
| | - Caroline S. Wechsler
- Department of Pediatric Oncology, Dana-Farber Cancer Institute and Boston Children's Hospital, Boston, Massachusetts
| | | | - Amanda L. Robichaud
- Department of Pediatric Oncology, Dana-Farber Cancer Institute and Boston Children's Hospital, Boston, Massachusetts
| | - Amy Saur Conway
- Department of Pediatric Oncology, Dana-Farber Cancer Institute and Boston Children's Hospital, Boston, Massachusetts
| | - Thelma Mashaka
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts
| | - Sarah Mouche
- Translational Research Centre in Onco-hematology, Faculty of Medicine, University of Geneva, Geneva, Switzerland
| | - Biniam Adane
- Department of Pediatric Oncology, Dana-Farber Cancer Institute and Boston Children's Hospital, Boston, Massachusetts.,The Broad Institute of MIT and Harvard, Cambridge, Massachusetts
| | - Jeremy A. Ryan
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts
| | - Joseph D. Mancias
- Department of Radiation Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts
| | - Scott T. Younger
- The Broad Institute of MIT and Harvard, Cambridge, Massachusetts
| | | | - Lynn H. Lee
- Division of Oncology, Cancer and Blood Disease Institute, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio.,Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, Ohio
| | - Mark Wunderlich
- Division of Experimental Hematology and Cancer Biology, Cancer and Blood Disease Institute, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio
| | - Anthony Letai
- The Broad Institute of MIT and Harvard, Cambridge, Massachusetts.,Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts
| | - Jérôme Tamburini
- Translational Research Centre in Onco-hematology, Faculty of Medicine, University of Geneva, Geneva, Switzerland
| | - Kimberly Stegmaier
- Department of Pediatric Oncology, Dana-Farber Cancer Institute and Boston Children's Hospital, Boston, Massachusetts.,The Broad Institute of MIT and Harvard, Cambridge, Massachusetts.,Corresponding Author: Kimberly Stegmaier, Dana-Farber Cancer Institute, 450 Brookline Avenue, Boston, MA 02215. Phone: 617-632-4438; E-mail:
| |
Collapse
|
|
16
|
Roberts A, Phuah P, Cheng S, Murphy KG. Targeting Enteroendocrine Cells to Treat Metabolic Disease. COMPREHENSIVE PHARMACOLOGY 2022:344-372. [DOI: 10.1016/b978-0-12-820472-6.00068-2] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/05/2025]
|
|
17
|
Burman A, Kaji I. Luminal Chemosensory Cells in the Small Intestine. Nutrients 2021; 13:nu13113712. [PMID: 34835968 PMCID: PMC8620795 DOI: 10.3390/nu13113712] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2021] [Revised: 10/19/2021] [Accepted: 10/20/2021] [Indexed: 12/23/2022] Open
Abstract
In addition to the small intestine's well-known function of nutrient absorption, the small intestine also plays a major role in nutrient sensing. Similar to taste sensors seen on the tongue, GPCR-coupled nutrient sensors are expressed throughout the intestinal epithelium and respond to nutrients found in the lumen. These taste receptors respond to specific ligands, such as digested carbohydrates, fats, and proteins. The activation of nutrient sensors in the intestine allows for the induction of signaling pathways needed for the digestive system to process an influx of nutrients. Such processes include those related to glucose homeostasis and satiety. Defects in intestinal nutrient sensing have been linked to a variety of metabolic disorders, such as type 2 diabetes and obesity. Here, we review recent updates in the mechanisms related to intestinal nutrient sensors, particularly in enteroendocrine cells, and their pathological roles in disease. Additionally, we highlight the emerging nutrient sensing role of tuft cells and recent work using enteroids as a sensory organ model.
Collapse
Affiliation(s)
- Andreanna Burman
- Cell and Developmental Biology and Epithelial Biology Center, Vanderbilt University School of Medicine, Nashville, TN 37232, USA;
| | - Izumi Kaji
- Epithelial Biology Center and Section of Surgical Sciences, Vanderbilt University Medical Center, Nashville, TN 37232, USA
- Correspondence:
| |
Collapse
|
|
18
|
Honda Y, Ozaki A, Iwaki M, Kobayashi T, Nogami A, Kessoku T, Ogawa Y, Tomeno W, Imajo K, Yoneda M, Saito S, Nagashima Y, Nakajima A. Protective effect of SGL5213, a potent intestinal sodium-glucose cotransporter 1 inhibitor, in nonalcoholic fatty liver disease in mice. J Pharmacol Sci 2021; 147:176-183. [PMID: 34384565 DOI: 10.1016/j.jphs.2021.07.002] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2021] [Revised: 06/21/2021] [Accepted: 07/05/2021] [Indexed: 12/17/2022] Open
Abstract
BACKGROUND Nonalcoholic fatty liver disease (NAFLD) is the most common chronic disease. SGL5213, which is minimally absorbed and is restricted to the intestinal tract, is a potent intestinal sodium-glucose cotransporter 1 (SGLT1) inhibitor. In this study, we investigated the protective effect of SGL5213 in a rodent model of NAFLD. METHODS Using a rodent model of NAFLD, we compared SGL5213 efficacy with miglitol, which is an α-glucosidase inhibitor. We used a high-fat and high-sucrose diet-induced NAFLD model. RESULTS SGL5213 and miglitol improved obesity, liver dysfunction, insulin resistance, and the NAFLD severity. To further investigate the effects of SGL5213, we analyzed the mRNA expression of genes involved in lipid metabolism, inflammation, and liver fibrosis, and cecal pH levels. SGL5213 and miglitol treatment significantly decreased mRNA expression of factors involved in inflammation and liver fibrosis. SGL5213 treatment significantly decreased cecal pH levels, which did not occur with miglitol. CONCLUSIONS SGL5213 had a protective effect on the pathogenesis of NAFLD in a rodent model. We considered that inhibiting glucose absorption and increasing glucose content in the gastrointestinal tract with SGL5213 might have contributed to the protective effect in NAFLD. SGL5213 is a promising therapeutic agent for NAFLD with obesity and insulin resistance.
Collapse
Affiliation(s)
- Yasushi Honda
- Department of Gastroenterology and Hepatology, Yokohama City University Graduate School of Medicine, Yokohama 236-0004, Japan
| | - Anna Ozaki
- Department of Gastroenterology and Hepatology, Yokohama City University Graduate School of Medicine, Yokohama 236-0004, Japan
| | - Michihiro Iwaki
- Department of Gastroenterology and Hepatology, Yokohama City University Graduate School of Medicine, Yokohama 236-0004, Japan
| | - Takashi Kobayashi
- Department of Gastroenterology and Hepatology, Yokohama City University Graduate School of Medicine, Yokohama 236-0004, Japan
| | - Asako Nogami
- Department of Gastroenterology and Hepatology, Yokohama City University Graduate School of Medicine, Yokohama 236-0004, Japan
| | - Takaomi Kessoku
- Department of Gastroenterology and Hepatology, Yokohama City University Graduate School of Medicine, Yokohama 236-0004, Japan
| | - Yuji Ogawa
- Department of Gastroenterology and Hepatology, Yokohama City University Graduate School of Medicine, Yokohama 236-0004, Japan
| | - Wataru Tomeno
- Department of Gastroenterology, International University of Health and Welfare Atami Hospital, Atami 413-0002, Japan
| | - Kento Imajo
- Department of Gastroenterology and Hepatology, Yokohama City University Graduate School of Medicine, Yokohama 236-0004, Japan
| | - Masato Yoneda
- Department of Gastroenterology and Hepatology, Yokohama City University Graduate School of Medicine, Yokohama 236-0004, Japan.
| | - Satoru Saito
- Department of Gastroenterology and Hepatology, Yokohama City University Graduate School of Medicine, Yokohama 236-0004, Japan
| | - Yoji Nagashima
- Department of Surgical Pathology, Tokyo Women's Medical University, Tokyo 162-8666, Japan
| | - Atsushi Nakajima
- Department of Gastroenterology and Hepatology, Yokohama City University Graduate School of Medicine, Yokohama 236-0004, Japan
| |
Collapse
|
|
19
|
Korfhage J, Skinner ME, Basu J, Greenson JK, Miller RA, Lombard DB. Canagliflozin increases intestinal adenoma burden in female Apc Min/+ mice. J Gerontol A Biol Sci Med Sci 2021; 77:215-220. [PMID: 34448851 DOI: 10.1093/gerona/glab254] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2021] [Indexed: 11/13/2022] Open
Abstract
The diabetes drug canagliflozin extends lifespan in male mice. Since malignant neoplasms are the major cause of death in most mouse strains, this observation suggests that canagliflozin might exert anti-neoplastic effects in male mice. Here, we treated a mouse neoplasia model, the adenoma-prone Apc Min/+ strain, with canagliflozin, to test the effects of this drug on intestinal tumor burden. Surprisingly, canagliflozin increased the total area of intestine involved by adenomas, an effect most marked in the distal intestine and in female mice. Immunohistochemical analysis suggested that canagliflozin may not influence adenoma growth via direct SGLT1/2 inhibition in neoplastic cells. Our results are most consistent with a model where canagliflozin aggravates adenoma development by altering the anatomic distribution of intestinal glucose absorption, as evidenced by increases in postprandial GLP-1 levels driven by delayed glucose absorption. We hypothesize that canagliflozin exacerbates adenomatosis in the Apc Min/+ model via complex, cell-non-autonomous mechanisms, and that sex differences in GLP-1 responses may in part underlie sexually dimorphic effects of this drug on lifespan.
Collapse
Affiliation(s)
- Justin Korfhage
- Department of Pathology, University of Michigan, Ann Arbor, MI, USA
| | - Mary E Skinner
- Department of Pathology, University of Michigan, Ann Arbor, MI, USA
| | - Jookta Basu
- Department of Pathology, University of Michigan, Ann Arbor, MI, USA
| | - Joel K Greenson
- Department of Pathology, University of Michigan, Ann Arbor, MI, USA
| | - Richard A Miller
- Department of Pathology, University of Michigan, Ann Arbor, MI, USA.,Geriatrics Center and Paul F. Glenn Center for Biology of Aging Research, University of Michigan, Ann Arbor, MI, USA
| | - David B Lombard
- Department of Pathology, University of Michigan, Ann Arbor, MI, USA.,Geriatrics Center and Paul F. Glenn Center for Biology of Aging Research, University of Michigan, Ann Arbor, MI, USA.,Rogel Cancer Center, University of Michigan, Ann Arbor MI, USA
| |
Collapse
|
|
20
|
Kishida K, Iida T, Yamada T, Toyoda Y. d-Allose is absorbed via sodium-dependent glucose cotransporter 1 (SGLT1) in the rat small intestine. Metabol Open 2021; 11:100112. [PMID: 34381987 PMCID: PMC8339219 DOI: 10.1016/j.metop.2021.100112] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2021] [Revised: 07/19/2021] [Accepted: 07/21/2021] [Indexed: 11/17/2022] Open
Abstract
d-Allose is the C3 epimer of d-glucose and has been reported to have beneficial health effects. The transporter mediating intestinal transport of d-allose is unknown. We examined whether d-allose is absorbed via sodium-dependent glucose cotransporter 1 (SGLT1) as well as via glucose transporter type 5 (GLUT5) using rats. For examination of absorption via SGLT1, KGA-2727, an SGLT1-specific inhibitor, and d-allose were orally administered. KGA-2727 blocked the increase of plasma d-allose levels and suppressed them throughout the experiment (0–180 min), whereas without KGA-2727, the plasma d-allose levels peaked at around 60–90 min. For examination of absorption via GLUT5, rats were fed a high-fructose diet for 3weeks to increase the abundance and activity of GLUT5 in the small intestine. High-fructose diet-fed rats did not exhibit significant changes in the plasma d-allose levels compared to control rats fed a high-glucose diet. These results indicate that SGLT1 but not GLUT5 mediates the intestinal absorption of d-allose.
Plasma d-allose levels were blocked by KGA-2727, an SGLT1-specific inhibitor. Fructose-fed rats which highly express intestinal GLUT5 did not exhibit significant changes in the plasma d-allose levels. SGLT1 clearly mediates intestinal d-allose transport.
Collapse
Affiliation(s)
- Kunihiro Kishida
- Department of Science and Technology on Food Safety, Kindai University, 930 Nishimitani, Kinokawa, Wakayama, 649-6493, Japan
| | - Tetsuo Iida
- Research and Development, Matsutani Chemical Industry Company, Limited, 5-3 Kita-Itami, Itami, Hyogo, 664-8508, Japan
| | - Takako Yamada
- Research and Development, Matsutani Chemical Industry Company, Limited, 5-3 Kita-Itami, Itami, Hyogo, 664-8508, Japan
| | - Yukiyasu Toyoda
- Department of Pathobiochemistry, Faculty of Pharmacy, Meijo University, 150 Yagotoyama, Tempaku-ku, Nagoya, Aichi, 468-8503, Japan
| |
Collapse
|
|
21
|
Lee CC, Chen WT, Chen SY, Lee TM. Dapagliflozin attenuates arrhythmic vulnerabilities by regulating connexin43 expression via the AMPK pathway in post-infarcted rat hearts. Biochem Pharmacol 2021; 192:114674. [PMID: 34252408 DOI: 10.1016/j.bcp.2021.114674] [Citation(s) in RCA: 25] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2021] [Revised: 06/28/2021] [Accepted: 07/06/2021] [Indexed: 12/13/2022]
Abstract
We have demonstrated that dapagliflozin, a sodium-glucose cotransporter (SGLT) 2 inhibitor, attenuates reactive oxygen species (ROS) production. Connexin43 playing a role in ventricular arrhythmia is sensitive to redox status. No data are available on the effects of dapagliflozin on arrhythmogenesis. This study was to determine whether dapagliflozin attenuated arrhythmias through modulating AMP-activated protein kinase (AMPK)/free radicals-induced connexin43 after myocardial infarction. After coronary ligation, normoglycemic male Wistar rats were randomized to either vehicle or dapagliflozin (0.1 mg/kg per day) for 4 weeks. Myocardial ROS levels were significantly increased (p < 0.05) and connexin43 levels were substantially decreased after myocardial infarction (p < 0.05). Dapagliflozin administration was associated with increased SGLT1, attenuated ROS and increased connexin43 levels in myocardium (all p < 0.05). During programmed electrical stimulation, arrhythmic severity was significantly improved in the dapagliflozin-treated infarcted rats than those in the vehicle-treated infarcted rats (p < 0.05). Dapagliflozin significantly increased AMPK phosphorylation compared to vehicle after infarction (p < 0.05). Inhibition of AMPK signaling by SBI-0206965 prevented increased SGLT1 and blocked the effects of dapagliflozin on attenuated ROS levels and increased connexin43 phosphorylation (all p < 0.05). SGLT1 inhibited by KGA-2727 showed attenuated ROS levels and increased connexin43 phosphorylation (both p < 0.05) although AMPK phosphorylation was not changed, implying SGLT1 activation was mediated by AMPK in dapagliflozin-treated hearts. Dapagliflozin-treated hearts had significantly increased connexin43 phosphorylation (p < 0.05), which was significantly decreased after adding 3-morpholinosydnonimine (p < 0.05). These data indicate that clinically-relevant dapagliflozin concentrations decreased free radicals content and increased connexin43 levels through AMPK-dependent and SGLT1-independent mechanisms, which attenuated ventricular arrhythmias in the normoglycemic infarcted rats.
Collapse
Affiliation(s)
| | - Wei-Ting Chen
- Cardiovascular Institute, An Nan Hospital, China Medical University, Tainan, Taiwan
| | - Syue-Yi Chen
- Cardiovascular Institute, An Nan Hospital, China Medical University, Tainan, Taiwan
| | - Tsung-Ming Lee
- Cardiovascular Institute, An Nan Hospital, China Medical University, Tainan, Taiwan; Department of Medicine, China Medical University, Taichung, Taiwan.
| |
Collapse
|
|
22
|
Shan X, Wang X, Jiang H, Cai C, Hao J, Yu G. Fucoidan from Ascophyllum nodosum Suppresses Postprandial Hyperglycemia by Inhibiting Na +/Glucose Cotransporter 1 Activity. Mar Drugs 2020; 18:E485. [PMID: 32971911 PMCID: PMC7551602 DOI: 10.3390/md18090485] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/13/2020] [Revised: 09/19/2020] [Accepted: 09/19/2020] [Indexed: 12/18/2022] Open
Abstract
We previously demonstrated that fucoidan with a type II structure inhibited postprandial hyperglycemia by suppressing glucose uptake, but the mechanism remains elusive. Here, we aimed to assess whether the effect of glucose absorption inhibition was related to the basic structure of fucoidans and preliminarily clarified the underlying mechanism. Fucoidans with type II structure and type I structure were prepared from Ascophyllumnodosum (AnF) or Laminariajaponica (LjF) and Kjellmaniellacrassifolia (KcF), respectively. The effects of various fucoidans on suppressing postprandial hyperglycemia were investigated using in vitro (Caco-2 monolayer model), semi-in vivo (everted gut sac model), and in vivo (oral glucose tolerance test, OGTT) assays. The results showed that only AnF with a type II structure, but not LjF or KcF with type I structure, could inhibit the glucose transport in the Caco-2 monolayer and everted gut sac models. A similar result was seen in the OGTT of Kunming mice and leptin receptor-deficient (db/db) mice, where only AnF could effectively inhibit glucose transport into the bloodstream. Furthermore, AnF (400 mg/kg/d) treatment decreased the fasting blood glucose, HbA1c, and fasting insulin levels, while increasing the serum glucagon-like peptide-1 (GLP-1) level in obese leptin receptor-deficient (db/db) mice. Furthermore, surface plasmon resonance (SPR) analysis revealed the specific binding of AnF to Na+/glucose cotransporter 1 (SGLT1), which indicated the effect of AnF on postprandial hyperglycemia could be due to its suppression on SGLT1 activity. Taken together, this study suggests that AnF with a type II structure can be a promising candidate for hyperglycemia treatment.
Collapse
Affiliation(s)
- Xindi Shan
- Key Laboratory of Marine Drugs of Ministry of Education, Shandong Provincial Key Laboratory of Glycoscience and Glycotechnology, School of Medicine and Pharmacy, Ocean University of China, Qingdao 266003, China; (X.S.); (X.W.); (H.J.); (C.C.)
- Laboratory for Marine Drugs and Bioproducts, Pilot National Laboratory for Marine Science and Technology (Qingdao), Qingdao 266237, China
| | - Xueliang Wang
- Key Laboratory of Marine Drugs of Ministry of Education, Shandong Provincial Key Laboratory of Glycoscience and Glycotechnology, School of Medicine and Pharmacy, Ocean University of China, Qingdao 266003, China; (X.S.); (X.W.); (H.J.); (C.C.)
- Laboratory for Marine Drugs and Bioproducts, Pilot National Laboratory for Marine Science and Technology (Qingdao), Qingdao 266237, China
| | - Hao Jiang
- Key Laboratory of Marine Drugs of Ministry of Education, Shandong Provincial Key Laboratory of Glycoscience and Glycotechnology, School of Medicine and Pharmacy, Ocean University of China, Qingdao 266003, China; (X.S.); (X.W.); (H.J.); (C.C.)
- Laboratory for Marine Drugs and Bioproducts, Pilot National Laboratory for Marine Science and Technology (Qingdao), Qingdao 266237, China
| | - Chao Cai
- Key Laboratory of Marine Drugs of Ministry of Education, Shandong Provincial Key Laboratory of Glycoscience and Glycotechnology, School of Medicine and Pharmacy, Ocean University of China, Qingdao 266003, China; (X.S.); (X.W.); (H.J.); (C.C.)
- Laboratory for Marine Drugs and Bioproducts, Pilot National Laboratory for Marine Science and Technology (Qingdao), Qingdao 266237, China
| | - Jiejie Hao
- Key Laboratory of Marine Drugs of Ministry of Education, Shandong Provincial Key Laboratory of Glycoscience and Glycotechnology, School of Medicine and Pharmacy, Ocean University of China, Qingdao 266003, China; (X.S.); (X.W.); (H.J.); (C.C.)
- Laboratory for Marine Drugs and Bioproducts, Pilot National Laboratory for Marine Science and Technology (Qingdao), Qingdao 266237, China
| | - Guangli Yu
- Key Laboratory of Marine Drugs of Ministry of Education, Shandong Provincial Key Laboratory of Glycoscience and Glycotechnology, School of Medicine and Pharmacy, Ocean University of China, Qingdao 266003, China; (X.S.); (X.W.); (H.J.); (C.C.)
- Laboratory for Marine Drugs and Bioproducts, Pilot National Laboratory for Marine Science and Technology (Qingdao), Qingdao 266237, China
| |
Collapse
|
|
23
|
Sano R, Shinozaki Y, Ohta T. Sodium-glucose cotransporters: Functional properties and pharmaceutical potential. J Diabetes Investig 2020; 11:770-782. [PMID: 32196987 PMCID: PMC7378437 DOI: 10.1111/jdi.13255] [Citation(s) in RCA: 88] [Impact Index Per Article: 17.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/03/2020] [Revised: 03/06/2020] [Accepted: 03/13/2020] [Indexed: 02/06/2023] Open
Abstract
Glucose is the most abundant monosaccharide, and an essential source of energy for most living cells. Glucose transport across the cell membrane is mediated by two types of transporters: facilitative glucose transporters (gene name: solute carrier 2A) and sodium-glucose cotransporters (SGLTs; gene name: solute carrier 5A). Each transporter has its own substrate specificity, distribution, and regulatory mechanisms. Recently, SGLT1 and SGLT2 have attracted much attention as therapeutic targets for various diseases. This review addresses the basal and functional properties of glucose transporters and SGLTs, and describes the pharmaceutical potential of SGLT1 and SGLT2.
Collapse
Affiliation(s)
- Ryuhei Sano
- Biological/Pharmacological Research LaboratoriesCentral Pharmaceutical Research InstituteJapan Tobacco IncTakatsukiJapan
| | - Yuichi Shinozaki
- Biological/Pharmacological Research LaboratoriesCentral Pharmaceutical Research InstituteJapan Tobacco IncTakatsukiJapan
| | - Takeshi Ohta
- Laboratory of Animal Physiology and Functional AnatomyGraduate School of AgricultureKyoto UniversityKyotoJapan
| |
Collapse
|
|
24
|
Martinussen C, Veedfald S, Dirksen C, Bojsen-Møller KN, Svane MS, Wewer Albrechtsen NJ, van Hall G, Kristiansen VB, Fenger M, Holst JJ, Madsbad S. The effect of acute dual SGLT1/SGLT2 inhibition on incretin release and glucose metabolism after gastric bypass surgery. Am J Physiol Endocrinol Metab 2020; 318:E956-E964. [PMID: 32182123 DOI: 10.1152/ajpendo.00023.2020] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
Enhanced meal-related enteroendocrine secretion, particularly of glucagon-like peptide-1 (GLP-1), contributes to weight-loss and improved glycemia after Roux-en-Y gastric bypass (RYGB). Dietary glucose drives GLP-1 and glucose-dependent insulinotropic polypeptide (GIP) secretion postoperatively. Understanding how glucose triggers incretin secretion following RYGB could lead to new treatments of diabetes and obesity. In vitro, incretin release depends on glucose absorption via sodium-glucose cotransporter 1 (SGLT1). We investigated the importance of SGLT1/SGLT2 for enteropancreatic hormone concentrations and glucose metabolism after RYGB in a randomized, controlled, crossover study. Ten RYGB-operated patients ingested 50 g of oral glucose with and without acute pretreatment with 600 mg of the SGLT1/SGLT2-inhibitor canagliflozin. Paracetamol and 3-O-methyl-d-glucopyranose (3-OMG) were added to the glucose drink to evaluate rates of intestinal entry and absorption of glucose, respectively. Blood samples were collected for 4 h. The primary outcome was 4-h plasma GLP-1 (incremental area-under the curve, iAUC). Secondary outcomes included glucose, GIP, insulin, and glucagon. Canagliflozin delayed glucose absorption (time-to-peak 3-OMG: 50 vs. 132 min, P < 0.01) but did not reduce iAUC GLP-1 (6,067 vs. 7,273·min·pmol-1·L-1, P = 0.23), although peak GLP-1 concentrations were lowered (-28%, P = 0.03). Canagliflozin reduced GIP (iAUC -28%, P = 0.01; peak concentrations -57%, P < 0.01), insulin, and glucose excursions, whereas plasma glucagon (AUC 3,216 vs. 4,160 min·pmol·L-1, P = 0.02) and amino acids were increased. In conclusion, acute SGLT1/SGLT2-inhibition during glucose ingestion did not reduce 4-h plasma GLP-1 responses in RYGB-patients but attenuated the early rise in GLP-1, GIP, and insulin, whereas late glucagon concentrations were increased. The results suggest that SGLT1-mediated glucose absorption contributes to incretin hormone secretion after RYGB.
Collapse
Affiliation(s)
- Christoffer Martinussen
- Department of Endocrinology, Hvidovre Hospital, Hvidovre, Denmark
- Danish Diabetes Academy, Odense, Denmark
- Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, Copenhagen, Denmark
| | - Simon Veedfald
- Department of Endocrinology, Hvidovre Hospital, Hvidovre, Denmark
- Department of Biomedical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Carsten Dirksen
- Department of Endocrinology, Hvidovre Hospital, Hvidovre, Denmark
- Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, Copenhagen, Denmark
| | - Kirstine N Bojsen-Møller
- Department of Endocrinology, Hvidovre Hospital, Hvidovre, Denmark
- Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, Copenhagen, Denmark
| | - Maria S Svane
- Department of Endocrinology, Hvidovre Hospital, Hvidovre, Denmark
- Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, Copenhagen, Denmark
| | - Nicolai J Wewer Albrechtsen
- Department of Biomedical Sciences, University of Copenhagen, Copenhagen, Denmark
- Department of Clinical Biochemistry, Rigshospitalet, Copenhagen, Denmark
| | - Gerrit van Hall
- Department of Biomedical Sciences, University of Copenhagen, Copenhagen, Denmark
- Clinical Metabolomics Core Facility, Clinical Biochemistry, Rigshospitalet, Copenhagen, Denmark
| | - Viggo B Kristiansen
- Department of Surgical Gastroenterology, Hvidovre Hospital, Hvidovre, Denmark
| | - Mogens Fenger
- Department of Clinical Biochemistry, Hvidovre Hospital, Hvidovre, Denmark
| | - Jens J Holst
- Department of Biomedical Sciences, University of Copenhagen, Copenhagen, Denmark
- Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, Copenhagen, Denmark
| | - Sten Madsbad
- Department of Endocrinology, Hvidovre Hospital, Hvidovre, Denmark
- Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, Copenhagen, Denmark
| |
Collapse
|
|
25
|
Powell DR, Zambrowicz B, Morrow L, Beysen C, Hompesch M, Turner S, Hellerstein M, Banks P, Strumph P, Lapuerta P. Sotagliflozin Decreases Postprandial Glucose and Insulin Concentrations by Delaying Intestinal Glucose Absorption. J Clin Endocrinol Metab 2020; 105:dgz258. [PMID: 31837264 PMCID: PMC7067537 DOI: 10.1210/clinem/dgz258] [Citation(s) in RCA: 38] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/31/2019] [Accepted: 12/12/2019] [Indexed: 01/14/2023]
Abstract
CONTEXT The effect of sotagliflozin (a dual sodium-glucose cotransporter [SGLT] 2 and SGLT1 inhibitor) on intestinal glucose absorption has not been investigated in humans. OBJECTIVE To measure rate of appearance of oral glucose (RaO) using a dual glucose tracer method following standardized mixed meals taken after single sotagliflozin or canagliflozin doses. SETTING Clinical research organization. DESIGN AND PARTICIPANTS In a double-blind, 3-period crossover study (NCT01916863), 24 healthy participants were randomized to 2 cohorts of 12 participants. Within each cohort, participants were randomly assigned single oral doses of either sotagliflozin 400 mg, canagliflozin 300 mg, or placebo on each of test days 1, 8, and 15. On test days, Cohort 1 had breakfast containing [6,6-2H2] glucose 0.25 hours postdose and lunch containing [1-2H1] glucose 5.25 hours postdose; Cohort 2 had breakfast containing no labeled glucose 0.25 hours postdose and lunch containing [6,6-2H2] glucose 4.25 hours postdose. All participants received a 10- to 15-hour continuous [U-13C6] glucose infusion starting 5 hours before their first [6,6-2H2] glucose-containing meal. MAIN OUTCOME RaO, postprandial glucose (PPG), and postprandial insulin. RESULTS Sotagliflozin and canagliflozin decreased area under the curve (AUC)0-1 hour and/or AUC0-2 hours for RaO, PPG, and insulin after breakfast and/or the 4.25-hour postdose lunch (P < .05 versus placebo). After the 5.25-hour postdose lunch, sotagliflozin lowered RaO AUC0-1 hour and PPG AUC0-5 hours versus both placebo and canagliflozin (P < .05). CONCLUSIONS Sotagliflozin delayed and blunted intestinal glucose absorption after meals, resulting in lower PPG and insulin levels, likely due to prolonged local inhibition of intestinal SGLT1 that persisted for ≥5 hours after dosing.
Collapse
Affiliation(s)
| | | | | | | | | | - Scott Turner
- Pliant Therapeutics, South San Francisco, California
| | | | | | - Paul Strumph
- Lexicon Pharmaceuticals, Inc, The Woodlands, Texas
- Metavant Sciences, Ltd., Durham, North Carolina
| | | |
Collapse
|
|
26
|
Shakya A, Chaudary SK, Garabadu D, Bhat HR, Kakoti BB, Ghosh SK. A Comprehensive Review on Preclinical Diabetic Models. Curr Diabetes Rev 2020; 16:104-116. [PMID: 31074371 DOI: 10.2174/1573399815666190510112035] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/30/2018] [Revised: 02/20/2019] [Accepted: 04/22/2019] [Indexed: 12/16/2022]
Abstract
BACKGROUND Preclinical experimental models historically play a critical role in the exploration and characterization of disease pathophysiology. Further, these in-vivo and in-vitro preclinical experiments help in target identification, evaluation of novel therapeutic agents and validation of treatments. INTRODUCTION Diabetes mellitus (DM) is a multifaceted metabolic disorder of multidimensional aetiologies with the cardinal feature of chronic hyperglycemia. To avoid or minimize late complications of diabetes and related costs, primary prevention and early treatment are therefore necessary. Due to its chronic manifestations, new treatment strategies need to be developed, because of the limited effectiveness of the current therapies. METHODS The study included electronic databases such as Pubmed, Web of Science and Scopus. The datasets were searched for entries of studies up to June, 2018. RESULTS A large number of in-vivo and in-vitro models have been presented for evaluating the mechanism of anti-hyperglycaemic effect of drugs in hormone-, chemically-, pathogen-induced animal models of diabetes mellitus. The advantages and limitations of each model have also been addressed in this review. CONCLUSION This review encompasses the wide pathophysiological and molecular mechanisms associated with diabetes, particularly focusing on the challenges associated with the evaluation and predictive validation of these models as ideal animal models for preclinical assessments and discovering new drugs and therapeutic agents for translational application in humans. This review may further contribute to discover a novel drug to treat diabetes more efficaciously with minimum or no side effects. Furthermore, it also highlights ongoing research and considers the future perspectives in the field of diabetes.
Collapse
Affiliation(s)
- Anshul Shakya
- Department of Pharmaceutical Sciences, School of Science and Engineering, Dibrugarh University, Dibrugarh - 786 004, Assam, India
| | - Sushil Kumar Chaudary
- Department of Pharmacology, University of the Free State, Bloemfontein 9300, South Africa
| | - Debapriya Garabadu
- Institute of Pharmaceutical Research, GLA University, Mathura - 281406, Uttar Pradesh, India
| | - Hans Raj Bhat
- Department of Pharmaceutical Sciences, School of Science and Engineering, Dibrugarh University, Dibrugarh - 786 004, Assam, India
| | - Bibhuti Bhusan Kakoti
- Department of Pharmaceutical Sciences, School of Science and Engineering, Dibrugarh University, Dibrugarh - 786 004, Assam, India
| | - Surajit Kumar Ghosh
- Department of Pharmaceutical Sciences, School of Science and Engineering, Dibrugarh University, Dibrugarh - 786 004, Assam, India
| |
Collapse
|
|
27
|
Kalra J, Mangali SB, Dasari D, Bhat A, Goyal S, Dhar I, Sriram D, Dhar A. SGLT1 inhibition boon or bane for diabetes-associated cardiomyopathy. Fundam Clin Pharmacol 2019; 34:173-188. [PMID: 31698522 DOI: 10.1111/fcp.12516] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2019] [Revised: 09/18/2019] [Accepted: 10/14/2019] [Indexed: 12/29/2022]
Abstract
Chronic hyperglycaemia is a peculiar feature of diabetes mellitus (DM). Sequential metabolic abnormalities accompanying glucotoxicity are some of its implications. Glucotoxicity most likely corresponds to the vascular intricacy and metabolic alterations, such as increased oxidation of free fatty acids and reduced glucose oxidation. More than half of those with diabetes also develop cardiac abnormalities due to unknown causes, posing a major threat to the currently available marketed preparations which are being used for treating these cardiac complications. Even though impairment in cardiac functioning is the principal cause of death in individuals with type 2 diabetes (T2D), reducing plasma glucose levels has little effect on cardiovascular disease (CVD) risk. In vitro and in vivo studies have demonstrated that inhibitors of sodium glucose transporter (SGLT) represent a putative therapeutic intervention for these pathological conditions. Several clinical trials have reported the efficacy of SGLT inhibitors as a novel and potent antidiabetic agent which along with its antihyperglycaemic activity possesses the potential of effectively treating its associated cardiac abnormalities. Thus, hereby, the present review highlights the role of SGLT inhibitors as a successful drug candidate for correcting the shifts in deregulation of cardiac energy substrate metabolism together with its role in treating diabetes-related cardiac perturbations.
Collapse
Affiliation(s)
- Jaspreet Kalra
- Department of Pharmacy, Birla Institute of Technology and Sciences (BITS) Pilani, Hyderabad Campus, Jawahar Nagar, Shameerpet, Hyderabad,, Andhra Pradesh, 500078, India
| | - Suresh Babu Mangali
- Department of Pharmacy, Birla Institute of Technology and Sciences (BITS) Pilani, Hyderabad Campus, Jawahar Nagar, Shameerpet, Hyderabad,, Andhra Pradesh, 500078, India
| | - Deepika Dasari
- Department of Pharmacy, Birla Institute of Technology and Sciences (BITS) Pilani, Hyderabad Campus, Jawahar Nagar, Shameerpet, Hyderabad,, Andhra Pradesh, 500078, India
| | - Audesh Bhat
- Centre for Molecular Biology, Central University of Jammu, Jammu, 181143, India
| | - Srashti Goyal
- Department of Pharmacy, Birla Institute of Technology and Sciences (BITS) Pilani, Hyderabad Campus, Jawahar Nagar, Shameerpet, Hyderabad,, Andhra Pradesh, 500078, India
| | - Indu Dhar
- Department of Clinical Science, University of Bergen, Bergen, 5009, Norway
| | - Dharamrajan Sriram
- Department of Pharmacy, Birla Institute of Technology and Sciences (BITS) Pilani, Hyderabad Campus, Jawahar Nagar, Shameerpet, Hyderabad,, Andhra Pradesh, 500078, India
| | - Arti Dhar
- Department of Pharmacy, Birla Institute of Technology and Sciences (BITS) Pilani, Hyderabad Campus, Jawahar Nagar, Shameerpet, Hyderabad,, Andhra Pradesh, 500078, India
| |
Collapse
|
|
28
|
Pretreatment with KGA-2727, a selective SGLT1 inhibitor, is protective against myocardial infarction-induced ventricular remodeling and heart failure in mice. J Pharmacol Sci 2019; 142:16-25. [PMID: 31776072 DOI: 10.1016/j.jphs.2019.11.001] [Citation(s) in RCA: 33] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2019] [Revised: 10/28/2019] [Accepted: 10/29/2019] [Indexed: 01/01/2023] Open
Abstract
Recent studies demonstrated that sodium-glucose co-transporter 1 (SGLT1) is associated with human ischemic cardiomyopathy. However, whether SGLT1 blockade is effective against ischemic cardiomyopathy is still uncertain. We examined the effects of KGA-2727, a selective SGLT1 inhibitor, on myocardial infarction (MI)-induced ischemic cardiomyopathy. To create MI, left anterior descending coronary artery (LAD) ligation with or without KGA-2727 administration was performed in C57BL/6J mice. Four weeks after the operation, all mice were investigated. Left ventricular fractional shortening (LVFS) was reduced and KGA-2727 significantly improved it in LAD-ligated MI mice. The cardiomyocyte diameter, and ANP, BNP, β-MHC, and IL-18 gene expressions significantly increased in LAD-ligated mouse left ventricles compared with those of sham-operated mouse left ventricles, and KGA-2727 inhibited increases in them. Myocardial fibrosis and upregulation of CTGF and MMP-3 gene expressions in the left ventricle were increased in LAD-ligated mice compared with sham-operated mice, and KGA-2727 decreased them in the LAD-ligated left ventricles. SGLT1 protein expression level was significantly higher in LAD-ligated compared with sham-operated mouse ventricles regardless of KGA-2727 treatment. These results suggest that KGA-2727 pretreatment protects against MI-induced left ventricular remodeling through SGLT1 blockade and that it may become a new pharmacological therapy for ischemia-induced cardiomyopathy.
Collapse
|
|
29
|
Pathogenetic factors involved in recurrent pregnancy loss from multiple aspects. Obstet Gynecol Sci 2019; 62:212-223. [PMID: 31338338 PMCID: PMC6629979 DOI: 10.5468/ogs.2019.62.4.212] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/27/2018] [Revised: 02/23/2019] [Accepted: 05/06/2019] [Indexed: 12/19/2022] Open
Abstract
Recurrent pregnancy loss (RPL) is a common complication in obstetrics, affecting about 5% of women of childbearing age. An increase in the number of abortions results in escalation in the risk of miscarriage. Although concentrated research has identified numerous causes for RPL, about 50% of them remain unexplained. Pregnancy is a complex process, comprising fertilization, implantation, organ and tissue differentiation, and fetal growth, which is effectively controlled by a number of both maternal and fetal factors. An example is the immune response, in which T cells and natural killer cells participate, and inflammation mediated by tumor necrosis factor or colony-stimulating factor, which hinders embryo implantation. Furthermore, vitamin D affects glucose metabolism and inhibits embryonic development, whereas microRNA has a negative effect on the gene expression of embryo implantation and development. This review examines the causes of RPL from multiple perspectives, and focuses on the numerous factors that may result in RPL.
Collapse
|
|
30
|
Io F, Gunji E, Koretsune H, Kato K, Sugisaki-Kitano M, Okumura-Kitajima L, Kimura K, Uchida S, Yamamoto K. SGL5213, a novel and potent intestinal SGLT1 inhibitor, suppresses intestinal glucose absorption and enhances plasma GLP-1 and GLP-2 secretion in rats. Eur J Pharmacol 2019; 853:136-144. [DOI: 10.1016/j.ejphar.2019.03.023] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2019] [Revised: 03/02/2019] [Accepted: 03/12/2019] [Indexed: 02/07/2023]
|
|
31
|
Zhang J, Wei J, Jiang S, Xu L, Wang L, Cheng F, Buggs J, Koepsell H, Vallon V, Liu R. Macula Densa SGLT1-NOS1-Tubuloglomerular Feedback Pathway, a New Mechanism for Glomerular Hyperfiltration during Hyperglycemia. J Am Soc Nephrol 2019; 30:578-593. [PMID: 30867247 DOI: 10.1681/asn.2018080844] [Citation(s) in RCA: 75] [Impact Index Per Article: 12.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2018] [Accepted: 01/27/2019] [Indexed: 01/11/2023] Open
Abstract
BACKGROUND Glomerular hyperfiltration is common in early diabetes and is considered a risk factor for later diabetic nephropathy. We propose that sodium-glucose cotransporter 1 (SGLT1) senses increases in luminal glucose at the macula densa, enhancing generation of neuronal nitric oxide synthase 1 (NOS1)-dependent nitric oxide (NO) in the macula densa and blunting the tubuloglomerular feedback (TGF) response, thereby promoting the rise in GFR. METHODS We used microperfusion, micropuncture, and renal clearance of FITC-inulin to examine the effects of tubular glucose on NO generation at the macula densa, TGF, and GFR in wild-type and macula densa-specific NOS1 knockout mice. RESULTS Acute intravenous injection of glucose induced hyperglycemia and glucosuria with increased GFR in mice. We found that tubular glucose blunts the TGF response in vivo and in vitro and stimulates NO generation at the macula densa. We also showed that SGLT1 is expressed at the macula densa; in the presence of tubular glucose, SGLT1 inhibits TGF and NO generation, but this action is blocked when the SGLT1 inhibitor KGA-2727 is present. In addition, we demonstrated that glucose increases NOS1 expression and NOS1 phosphorylation at Ser1417 in mouse renal cortex and cultured human kidney tissue. In macula densa-specific NOS1 knockout mice, glucose had no effect on NO generation, TGF, and GFR. CONCLUSIONS We identified a novel mechanism of acute hyperglycemia-induced hyperfiltration wherein increases in luminal glucose at the macula densa upregulate the expression and activity of NOS1 via SGLT1, blunting the TGF response and promoting glomerular hyperfiltration.
Collapse
Affiliation(s)
- Jie Zhang
- Department of Molecular Pharmacology and Physiology, College of Medicine,
| | - Jin Wei
- Department of Molecular Pharmacology and Physiology, College of Medicine
| | - Shan Jiang
- Department of Molecular Pharmacology and Physiology, College of Medicine
| | - Lan Xu
- Department of Biostatistics, College of Public Health, and
| | - Lei Wang
- Department of Molecular Pharmacology and Physiology, College of Medicine
| | - Feng Cheng
- Department of Pharmaceutical Science, College of Pharmacy, University of South Florida, Tampa, Florida
| | - Jacentha Buggs
- Advanced Organ Disease & Transplantation Institute, Tampa General Hospital, Tampa, Florida
| | - Hermann Koepsell
- Institute of Anatomy and Cell Biology, University of Würzburg, Würzburg, Germany; and
| | - Volker Vallon
- Division of Nephrology and Hypertension, Department of Medicine, University of California, San Diego, La Jolla, California
| | - Ruisheng Liu
- Department of Molecular Pharmacology and Physiology, College of Medicine
| |
Collapse
|
|
32
|
Schäfer N, Rikkala PR, Veyhl-Wichmann M, Keller T, Jurowich CF, Geiger D, Koepsell H. A Modified Tripeptide Motif of RS1 ( RSC1A1) Down-Regulates Exocytotic Pathways of Human Na +-d-glucose Cotransporters SGLT1, SGLT2, and Glucose Sensor SGLT3 in the Presence of Glucose. Mol Pharmacol 2019; 95:82-96. [PMID: 30355744 DOI: 10.1124/mol.118.113514] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2018] [Accepted: 10/19/2018] [Indexed: 12/11/2022] Open
Abstract
A domain of protein RS1 (RSC1A1) called RS1-Reg down-regulates the plasma membrane abundance of Na+-d-glucose cotransporter SGLT1 by blocking the exocytotic pathway at the trans-Golgi. This effect is blunted by intracellular glucose but prevails when serine in a QSP (Gln-Ser-Pro) motif is replaced by glutamate [RS1-Reg(S20E)]. RS1-Reg binds to ornithine decarboxylase (ODC) and inhibits ODC in a glucose-dependent manner. Because the ODC inhibitor difluoromethylornithine (DFMO) acts like RS1-Reg(S20E), and DFMO and RS1-Reg(S20E) are not cumulative, we raised the hypothesis that RS1-Reg(S20E) down-regulates the exocytotic pathway of SGLT1 at the trans-Golgi by inhibiting ODC. We investigated whether QEP down-regulates human SGLT1 (hSGLT1) like hRS1-Reg(S20E) and whether human Na+-d-glucose cotransporter hSGLT2 and the human glucose sensor hSGLT3 are also addressed. We expressed hSGLT1, hSGLT1 linked to yellow fluorescent protein (hSGLT1-YFP), hSGLT2-YFP and hSGLT3-YFP in oocytes of Xenopus laevis, injected hRS1-Reg(S20E), QEP, DFMO, and/or α-methyl-d-glucopyranoside (AMG), and measured AMG uptake, glucose-induced currents, and plasma membrane-associated fluorescence after 1 hour. We also performed in vitro AMG uptake measurements into small intestinal mucosa of mice and human. The data indicate that QEP down-regulates the exocytotic pathway of SGLT1 similar to hRS1-Reg(S20E). Our results suggests that both peptides also down-regulate hSGLT2 and hSGLT3 via the same pathway. Thirty minutes after application of 5 mM QEP in the presence of 5 mM d-glucose, hSGLT1-mediated AMG uptake into small intestinal mucosa was decreased by 40% to 50%. Thus oral application of QEP in a formulation that optimizes uptake into enterocytes but prevents entry into the blood is proposed as novel antidiabetic therapy.
Collapse
Affiliation(s)
- Nadine Schäfer
- Department of Molecular Plant Physiology and Biophysics, Julius-von-Sachs-Institute (N.S., T.K., D.G., H.K.) and Institute of Anatomy and Cell Biology (P.R.R., M.V.-W., H.K.), University of Würzburg, Würzburg, Germany; and Department of General, Visceral, Vascular, and Paedriatic Surgery, University Hospital of Würzburg, Würzburg, Germany (C.F.J.)
| | - Prashanth Reddy Rikkala
- Department of Molecular Plant Physiology and Biophysics, Julius-von-Sachs-Institute (N.S., T.K., D.G., H.K.) and Institute of Anatomy and Cell Biology (P.R.R., M.V.-W., H.K.), University of Würzburg, Würzburg, Germany; and Department of General, Visceral, Vascular, and Paedriatic Surgery, University Hospital of Würzburg, Würzburg, Germany (C.F.J.)
| | - Maike Veyhl-Wichmann
- Department of Molecular Plant Physiology and Biophysics, Julius-von-Sachs-Institute (N.S., T.K., D.G., H.K.) and Institute of Anatomy and Cell Biology (P.R.R., M.V.-W., H.K.), University of Würzburg, Würzburg, Germany; and Department of General, Visceral, Vascular, and Paedriatic Surgery, University Hospital of Würzburg, Würzburg, Germany (C.F.J.)
| | - Thorsten Keller
- Department of Molecular Plant Physiology and Biophysics, Julius-von-Sachs-Institute (N.S., T.K., D.G., H.K.) and Institute of Anatomy and Cell Biology (P.R.R., M.V.-W., H.K.), University of Würzburg, Würzburg, Germany; and Department of General, Visceral, Vascular, and Paedriatic Surgery, University Hospital of Würzburg, Würzburg, Germany (C.F.J.)
| | - Christian Ferdinand Jurowich
- Department of Molecular Plant Physiology and Biophysics, Julius-von-Sachs-Institute (N.S., T.K., D.G., H.K.) and Institute of Anatomy and Cell Biology (P.R.R., M.V.-W., H.K.), University of Würzburg, Würzburg, Germany; and Department of General, Visceral, Vascular, and Paedriatic Surgery, University Hospital of Würzburg, Würzburg, Germany (C.F.J.)
| | - Dietmar Geiger
- Department of Molecular Plant Physiology and Biophysics, Julius-von-Sachs-Institute (N.S., T.K., D.G., H.K.) and Institute of Anatomy and Cell Biology (P.R.R., M.V.-W., H.K.), University of Würzburg, Würzburg, Germany; and Department of General, Visceral, Vascular, and Paedriatic Surgery, University Hospital of Würzburg, Würzburg, Germany (C.F.J.)
| | - Hermann Koepsell
- Department of Molecular Plant Physiology and Biophysics, Julius-von-Sachs-Institute (N.S., T.K., D.G., H.K.) and Institute of Anatomy and Cell Biology (P.R.R., M.V.-W., H.K.), University of Würzburg, Würzburg, Germany; and Department of General, Visceral, Vascular, and Paedriatic Surgery, University Hospital of Würzburg, Würzburg, Germany (C.F.J.)
| |
Collapse
|
|
33
|
Lee KH, Lee SD, Kim N, Suh KH, Kim YH, Sim SS. Pharmacological evaluation of HM41322, a novel SGLT1/2 dual inhibitor, in vitro and in vivo. THE KOREAN JOURNAL OF PHYSIOLOGY & PHARMACOLOGY : OFFICIAL JOURNAL OF THE KOREAN PHYSIOLOGICAL SOCIETY AND THE KOREAN SOCIETY OF PHARMACOLOGY 2018; 23:55-62. [PMID: 30627010 PMCID: PMC6315097 DOI: 10.4196/kjpp.2019.23.1.55] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/11/2018] [Revised: 10/16/2018] [Accepted: 10/29/2018] [Indexed: 12/20/2022]
Abstract
HM41322 is a novel oral sodium-glucose cotransporter (SGLT) 1/2 dual inhibitor. In this study, the in vitro and in vivo pharmacokinetic and pharmacologic profiles of HM41322 were compared to those of dapagliflozin. HM41322 showed a 10-fold selectivity for SGLT2 over SGLT1. HM41322 showed an inhibitory effect on SGLT2 similar to dapagliflozin, but showed a more potent inhibitory effect on SGLT1 than dapagliflozin. The maximum plasma HM41322 level after single oral doses at 0.1, 1, and 3 mg/kg were 142, 439, and 1830 ng/ml, respectively, and the T1/2 was 3.1 h. HM41322 was rapidly absorbed and reached the circulation within 15 min. HM41322 maximized urinary glucose excretion by inhibiting both SGLT1 and SGLT2 in the kidney. HM41322 3 mg/kg caused the maximum urinary glucose excretion in normoglycemic mice (19.32±1.16 mg/g) at 24 h. In normal and diabetic mice, HM41322 significantly reduced glucose excursion. Four-week administration of HM41322 in db/db mice reduced HbA1c in a dose dependent manner. Taken together, HM41322 showed a favorable preclinical profile of postprandial glucose control through dual inhibitory activities against SGLT1 and SGLT2.
Collapse
Affiliation(s)
- Kyu Hang Lee
- Hanmi Research Center, Hanmi Pharmaceutical Co., Ltd, Hwaseong 18469, Korea
| | - Sang Don Lee
- Hanmi Research Center, Hanmi Pharmaceutical Co., Ltd, Hwaseong 18469, Korea
| | - Namdu Kim
- Hanmi Research Center, Hanmi Pharmaceutical Co., Ltd, Hwaseong 18469, Korea
| | - Kwee Hyun Suh
- Hanmi Research Center, Hanmi Pharmaceutical Co., Ltd, Hwaseong 18469, Korea
| | - Young Hoon Kim
- Hanmi Research Center, Hanmi Pharmaceutical Co., Ltd, Hwaseong 18469, Korea
| | - Sang Soo Sim
- College of Pharmacy, Chung-Ang University, Seoul 06974, Korea
| |
Collapse
|
|
34
|
Gonzalez-Vicente A, Cabral PD, Hong NJ, Asirwatham J, Saez F, Garvin JL. Fructose reabsorption by rat proximal tubules: role of Na +-linked cotransporters and the effect of dietary fructose. Am J Physiol Renal Physiol 2018; 316:F473-F480. [PMID: 30565998 DOI: 10.1152/ajprenal.00247.2018] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022] Open
Abstract
Fructose consumption has increased because of widespread use of high-fructose corn syrup by the food industry. Renal proximal tubules are thought to reabsorb fructose. However, fructose reabsorption (Jfructose) by proximal tubules has not yet been directly demonstrated, nor the effects of dietary fructose on Jfructose. This segment expresses Na+- and glucose-linked transporters (SGLTs) 1, 2, 4, and 5 and glucose transporters (GLUTs) 2 and 5. SGLT4 and -5 transport fructose, but SGLT1 and -2 do not. Knocking out SGLT5 increases urinary fructose excretion. We hypothesize that Jfructose in the S2 portion of the proximal tubule is mediated by luminal entry via SGLT4/5 and basolateral exit by GLUT2 and that it is enhanced by a fructose-enriched diet. We measured Jfructose by proximal straight tubules from rats consuming either tap water (Controls) or 20% fructose (FRU). Basal Jfructose in Controls was 14.1 ± 1.5 pmol·mm-1·min-1. SGLT inhibition with phlorizin reduced Jfructose to 4.9 ± 1.4 pmol·mm-1·min-1 ( P < 0.008), whereas removal of Na+ diminished Jfructose by 86 ± 5% ( P < 0.0001). A fructose-enriched diet increased Jfructose from 12.8 ± 2.5 to 19.3 ± 0.5 pmol·mm-1·min-1, a 51% increase ( P < 0.03). Using immunofluorescence, we detected luminal SGLT4 and SGLT5 and basolateral GLUT2; GLUT5 was undetectable. The expression of apical transporters SGLT4 and SGLT5 was higher in FRU than in Controls [137 ± 10% ( P < 0.01) and 38 ± 14% ( P < 0.04), respectively]. GLUT2 was also elevated by 88 ± 27% ( P < 0.02) in FRU. We conclude that Jfructose by proximal tubules occurs primarily via Na+-linked cotransport processes, and a fructose-enriched diet enhances reabsorption. Transport across luminal and basolateral membranes is likely mediated by SGLT4/5 and GLUT2, respectively.
Collapse
Affiliation(s)
- Agustin Gonzalez-Vicente
- Department of Physiology and Biophysics, School of Medicine, Case Western Reserve University , Cleveland, Ohio.,Facultad de Farmacia y Bioquímica, Universidad de Buenos Aires, Ciudad Autónoma de Buenos Aires, Argentina
| | - Pablo D Cabral
- Department of Physiology and Biophysics, School of Medicine, Case Western Reserve University , Cleveland, Ohio.,Facultad de Medicina, Departamento de Ciencias Fisiológicas, Universidad de Buenos Aires, Ciudad Autónoma de Buenos Aires, Argentina
| | - Nancy J Hong
- Department of Physiology and Biophysics, School of Medicine, Case Western Reserve University , Cleveland, Ohio
| | - Jessica Asirwatham
- Department of Physiology and Biophysics, School of Medicine, Case Western Reserve University , Cleveland, Ohio
| | - Fara Saez
- Department of Physiology and Biophysics, School of Medicine, Case Western Reserve University , Cleveland, Ohio
| | - Jeffrey L Garvin
- Department of Physiology and Biophysics, School of Medicine, Case Western Reserve University , Cleveland, Ohio
| |
Collapse
|
|
35
|
Wang N, Li S, Guo XC, Li JY, Ren GP, Li DS. Fibroblast growth factor 21 improves glucose homeostasis partially via down-regulation of Na +-d-glucose cotransporter SGLT1 in the small intestine. Biomed Pharmacother 2018; 109:1070-1077. [PMID: 30551357 DOI: 10.1016/j.biopha.2018.10.198] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2018] [Revised: 10/26/2018] [Accepted: 10/31/2018] [Indexed: 12/15/2022] Open
Abstract
Fibroblast growth factor-21 (FGF-21), an endocrine hormone, is regarded as a therapeutic target for diabetes base on its potent effects on improving hyperglycemia. Sodium-dependent glucose cotransporter 1 (SGLT1) is mainly expressed in the small intestine (SI) for intestinal glucose absorption. It has been demonstrated that SGLT1 expression is increased in diabetes, which is thought to contribute to the rapidly rising postprandial blood glucose levels. Thus, we aim to examine whether FGF-21 regulates expression of intestinal SGLT1 in diabetes. The db/db mice were treated with insulin, low and high dose of FGF-21 for 5 weeks and then measured changes in glucose metabolism, intestinal glucose absorption and SGLT1 expression. The results showed that FGF-21 improved glucose homeostasis, inhibited intestinal glucose uptake and reduced intestinal SGLT1 expression compared with insulin in db/db mice. To further explore the mechanism of effects of FGF-21 on SGLT1 expression. The murine intestinal epithelial MODE-K cells were treated with FGF-21 for 3 h, 6 h, 12 h and 24 h and then measured glucose uptake, SGLT1 expression, another glucose transporter GLUT2 expression and associated mechanism. Our results showed that FGF-21 inhibited glucose uptake and reduced SGLT1 expression in MODE-K cells, which were due to inactivating SGK-1 pathway. Moreover, above effects of FGF-21 on MODE-K cells were abolished by PD173074, a FGFR1 inhibitor. In conclusion, FGF-21 regulates glucose level in diabetes partially due to inhibiting glucose absorption in the SI via inactivating SGK-1 pathway. These results expand our knowledge about how FGF-21 regulates glucose metabolism.
Collapse
Affiliation(s)
- Nan Wang
- Biopharmaceutical Lab, Life Science college, Northeast Agricultural University, Harbin 150030, China
| | - Shuai Li
- Biopharmaceutical Lab, Life Science college, Northeast Agricultural University, Harbin 150030, China
| | - Xiao-Chen Guo
- Biopharmaceutical Lab, Life Science college, Northeast Agricultural University, Harbin 150030, China
| | - Jun-Yan Li
- Biopharmaceutical Lab, Life Science college, Northeast Agricultural University, Harbin 150030, China
| | - Gui-Ping Ren
- Biopharmaceutical Lab, Life Science college, Northeast Agricultural University, Harbin 150030, China; Key Laboratory of Agricultural Biological Functional Gene, Northeast Agricultural University, Harbin, 150030, China
| | - De-Shan Li
- Biopharmaceutical Lab, Life Science college, Northeast Agricultural University, Harbin 150030, China; Key Laboratory of Agricultural Biological Functional Gene, Northeast Agricultural University, Harbin, 150030, China.
| |
Collapse
|
|
36
|
Seidelmann SB, Feofanova E, Yu B, Franceschini N, Claggett B, Kuokkanen M, Puolijoki H, Ebeling T, Perola M, Salomaa V, Shah A, Coresh J, Selvin E, MacRae CA, Cheng S, Boerwinkle E, Solomon SD. Genetic Variants in SGLT1, Glucose Tolerance, and Cardiometabolic Risk. J Am Coll Cardiol 2018; 72:1763-1773. [PMID: 30286918 PMCID: PMC6403489 DOI: 10.1016/j.jacc.2018.07.061] [Citation(s) in RCA: 56] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/25/2018] [Revised: 07/11/2018] [Accepted: 07/15/2018] [Indexed: 12/30/2022]
Abstract
BACKGROUND Loss-of-function mutations in the SGLT1 (sodium/glucose co-transporter-1) gene result in a rare glucose/galactose malabsorption disorder and neonatal death if untreated. In the general population, variants related to intestinal glucose absorption remain uncharacterized. OBJECTIVES The goal of this study was to identify functional SGLT1 gene variants and characterize their clinical consequences. METHODS Whole exome sequencing was performed in the ARIC (Atherosclerosis Risk in Communities) study participants enrolled from 4 U.S. communities. The association of functional, nonsynonymous substitutions in SGLT1 with 2-h oral glucose tolerance test results was determined. Variants related to impaired glucose tolerance were studied, and Mendelian randomization analysis of cardiometabolic outcomes was performed. RESULTS Among 5,687 European-American subjects (mean age 54 ± 6 years; 47% male), those who carried a haplotype of 3 missense mutations (frequency of 6.7%)-Asn51Ser, Ala411Thr, and His615Gln-had lower 2-h glucose and odds of impaired glucose tolerance than noncarriers (β-coefficient: -8.0; 95% confidence interval [CI]: -12.7 to -3.3; OR: 0.71; 95% CI: 0.59 to 0.86, respectively). The association of the haplotype with oral glucose tolerance test results was consistent in a replication sample of 2,791 African-American subjects (β = -16.3; 95% CI: -36.6 to 4.1; OR: 0.39; 95% CI: 0.17 to 0.91) and an external European-Finnish population sample of 6,784 subjects (β = -3.2; 95% CI: -6.4 to -0.02; OR: 0.81; 95% CI: 0.68 to 0.98). Using a Mendelian randomization approach in the index cohort, the estimated 25-year effect of a reduction of 20 mg/dl in 2-h glucose via SGLT1 inhibition would be reduced prevalent obesity (OR: 0.43; 95% CI: 0.23 to 0.63), incident diabetes (hazard ratio [HR]: 0.58; 95% CI: 0.35 to 0.81), heart failure (HR: 0.53; 95% CI: 0.24 to 0.83), and death (HR: 0.66; 95% CI: 0.42 to 0.90). CONCLUSIONS Functionally damaging missense variants in SGLT1 protect from diet-induced hyperglycemia in multiple populations. Reduced intestinal glucose uptake may protect from long-term cardiometabolic outcomes, providing support for therapies that target SGLT1 function to prevent and treat metabolic conditions.
Collapse
Affiliation(s)
- Sara B Seidelmann
- Cardiovascular Division, Harvard Medical School and Brigham and Women's Hospital, Boston, Massachusetts; Division of Cardiovascular Imaging, Harvard Medical School and Brigham and Women's Hospital, Boston, Massachusetts
| | - Elena Feofanova
- Epidemiology, Human Genetics & Environmental Sciences, UTHealth School of Public Health, Houston, Texas
| | - Bing Yu
- Epidemiology, Human Genetics & Environmental Sciences, UTHealth School of Public Health, Houston, Texas
| | - Nora Franceschini
- Department of Epidemiology, UNC Gilling Global School of Public Health, Chapel Hill, North Carolina
| | - Brian Claggett
- Cardiovascular Division, Harvard Medical School and Brigham and Women's Hospital, Boston, Massachusetts
| | - Mikko Kuokkanen
- National Institute for Health and Welfare, Helsinki, Finland; University of Helsinki, Diabetes and Obesity Research Program, Helsinki, Finland
| | | | - Tapani Ebeling
- Department of Medicine, Oulu University Hospital and University of Oulu, Oulu, Finland
| | - Markus Perola
- National Institute for Health and Welfare, Helsinki, Finland; University of Helsinki, Diabetes and Obesity Research Program, Helsinki, Finland
| | - Veikko Salomaa
- National Institute for Health and Welfare, Helsinki, Finland
| | - Amil Shah
- Cardiovascular Division, Harvard Medical School and Brigham and Women's Hospital, Boston, Massachusetts
| | - Josef Coresh
- Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, and Welch Center for Prevention, Epidemiology, and Clinical Research and Division of General Internal Medicine, Department of Medicine, Johns Hopkins School of Medicine, Baltimore, Maryland
| | - Elizabeth Selvin
- Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, and Welch Center for Prevention, Epidemiology, and Clinical Research and Division of General Internal Medicine, Department of Medicine, Johns Hopkins School of Medicine, Baltimore, Maryland
| | - Calum A MacRae
- Cardiovascular Division, Harvard Medical School and Brigham and Women's Hospital, Boston, Massachusetts
| | - Susan Cheng
- Cardiovascular Division, Harvard Medical School and Brigham and Women's Hospital, Boston, Massachusetts
| | - Eric Boerwinkle
- Epidemiology, Human Genetics & Environmental Sciences, UTHealth School of Public Health, Houston, Texas; Human Genome Sequencing Center, Baylor College of Medicine, Houston, Texas
| | - Scott D Solomon
- Cardiovascular Division, Harvard Medical School and Brigham and Women's Hospital, Boston, Massachusetts.
| |
Collapse
|
|
37
|
Du F, Hinke SA, Cavanaugh C, Polidori D, Wallace N, Kirchner T, Jennis M, Lang W, Kuo GH, Gaul MD, Lenhard J, Demarest K, Ajami NJ, Liang Y, Hornby PJ. Potent Sodium/Glucose Cotransporter SGLT1/2 Dual Inhibition Improves Glycemic Control Without Marked Gastrointestinal Adaptation or Colonic Microbiota Changes in Rodents. J Pharmacol Exp Ther 2018; 365:676-687. [PMID: 29674332 DOI: 10.1124/jpet.118.248575] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2018] [Accepted: 03/22/2018] [Indexed: 02/06/2023] Open
Abstract
The sodium/glucose cotransporters (SGLT1 and SGLT2) transport glucose across the intestinal brush border and kidney tubule. Dual SGLT1/2 inhibition could reduce hyperglycemia more than SGLT2-selective inhibition in patients with type 2 diabetes. However, questions remain about altered gastrointestinal (GI) luminal glucose and tolerability, and this was evaluated in slc5a1-/- mice or with a potent dual inhibitor (compound 8; SGLT1 Ki = 1.5 ± 0.5 nM 100-fold greater potency than phlorizin; SGLT2 Ki = 0.4 ± 0.2 nM). 13C6-glucose uptake was quantified in slc5a1-/- mice and in isolated rat jejunum. Urinary glucose excretion (UGE), blood glucose (Sprague-Dawley rats), glucagon-like peptide 1 (GLP-1), and hemoglobin A1c (HbA1c) levels (Zucker diabetic fatty rats) were measured. Intestinal adaptation and rRNA gene sequencing was analyzed in C57Bl/6 mice. The blood 13C6-glucose area under the curve (AUC) was reduced in the absence of SGLT1 by 75% (245 ± 6 vs. 64 ± 6 mg/dl⋅h in wild-type vs. slc5a1-/- mice) and compound 8 inhibited its transport up to 50% in isolated rat jejunum. Compound 8 reduced glucose excursion more than SGLT2-selective inhibition (e.g., AUC = 129 ± 3 vs. 249 ± 5 mg/dl⋅h for 1 mg/kg compound 8 vs. dapagliflozin) with similar UGE but a lower renal glucose excretion threshold. In Zucker diabetic fatty rats, compound 8 decreased HbA1c and increased total GLP-1 without changes in jejunum SGLT1 expression, mucosal weight, or villus length. Overall, compound 8 (1 mg/kg for 6 days) did not increase cecal glucose concentrations or bacterial diversity in C57BL/6 mice. In conclusion, potent dual SGLT1/2 inhibition lowers blood glucose by reducing intestinal glucose absorption and the renal glucose threshold but minimally impacts the intestinal mucosa or luminal microbiota in chow-fed rodents.
Collapse
Affiliation(s)
- Fuyong Du
- Cardiovascular and Metabolism Discovery (F.D., S.A.H., C.C., N.W., T.K., M.J., G.-H.K., M.D.G., J.L., K.D., Y.L., P.J.H.) and Analytical Sciences (W.L.), Janssen R&D LLC, Spring House, Pennsylvania; Cardiovascular and Metabolism Experimental and Translational Medicine, Janssen R&D LLC, San Diego, California (D.P.); and Alkek Center for Metagenomics and Microbiome Research, Department of Molecular Virology and Microbiology, Baylor College of Medicine, Houston, Texas (N.J.A.)
| | - Simon A Hinke
- Cardiovascular and Metabolism Discovery (F.D., S.A.H., C.C., N.W., T.K., M.J., G.-H.K., M.D.G., J.L., K.D., Y.L., P.J.H.) and Analytical Sciences (W.L.), Janssen R&D LLC, Spring House, Pennsylvania; Cardiovascular and Metabolism Experimental and Translational Medicine, Janssen R&D LLC, San Diego, California (D.P.); and Alkek Center for Metagenomics and Microbiome Research, Department of Molecular Virology and Microbiology, Baylor College of Medicine, Houston, Texas (N.J.A.)
| | - Cassandre Cavanaugh
- Cardiovascular and Metabolism Discovery (F.D., S.A.H., C.C., N.W., T.K., M.J., G.-H.K., M.D.G., J.L., K.D., Y.L., P.J.H.) and Analytical Sciences (W.L.), Janssen R&D LLC, Spring House, Pennsylvania; Cardiovascular and Metabolism Experimental and Translational Medicine, Janssen R&D LLC, San Diego, California (D.P.); and Alkek Center for Metagenomics and Microbiome Research, Department of Molecular Virology and Microbiology, Baylor College of Medicine, Houston, Texas (N.J.A.)
| | - David Polidori
- Cardiovascular and Metabolism Discovery (F.D., S.A.H., C.C., N.W., T.K., M.J., G.-H.K., M.D.G., J.L., K.D., Y.L., P.J.H.) and Analytical Sciences (W.L.), Janssen R&D LLC, Spring House, Pennsylvania; Cardiovascular and Metabolism Experimental and Translational Medicine, Janssen R&D LLC, San Diego, California (D.P.); and Alkek Center for Metagenomics and Microbiome Research, Department of Molecular Virology and Microbiology, Baylor College of Medicine, Houston, Texas (N.J.A.)
| | - Nathanial Wallace
- Cardiovascular and Metabolism Discovery (F.D., S.A.H., C.C., N.W., T.K., M.J., G.-H.K., M.D.G., J.L., K.D., Y.L., P.J.H.) and Analytical Sciences (W.L.), Janssen R&D LLC, Spring House, Pennsylvania; Cardiovascular and Metabolism Experimental and Translational Medicine, Janssen R&D LLC, San Diego, California (D.P.); and Alkek Center for Metagenomics and Microbiome Research, Department of Molecular Virology and Microbiology, Baylor College of Medicine, Houston, Texas (N.J.A.)
| | - Thomas Kirchner
- Cardiovascular and Metabolism Discovery (F.D., S.A.H., C.C., N.W., T.K., M.J., G.-H.K., M.D.G., J.L., K.D., Y.L., P.J.H.) and Analytical Sciences (W.L.), Janssen R&D LLC, Spring House, Pennsylvania; Cardiovascular and Metabolism Experimental and Translational Medicine, Janssen R&D LLC, San Diego, California (D.P.); and Alkek Center for Metagenomics and Microbiome Research, Department of Molecular Virology and Microbiology, Baylor College of Medicine, Houston, Texas (N.J.A.)
| | - Matthew Jennis
- Cardiovascular and Metabolism Discovery (F.D., S.A.H., C.C., N.W., T.K., M.J., G.-H.K., M.D.G., J.L., K.D., Y.L., P.J.H.) and Analytical Sciences (W.L.), Janssen R&D LLC, Spring House, Pennsylvania; Cardiovascular and Metabolism Experimental and Translational Medicine, Janssen R&D LLC, San Diego, California (D.P.); and Alkek Center for Metagenomics and Microbiome Research, Department of Molecular Virology and Microbiology, Baylor College of Medicine, Houston, Texas (N.J.A.)
| | - Wensheng Lang
- Cardiovascular and Metabolism Discovery (F.D., S.A.H., C.C., N.W., T.K., M.J., G.-H.K., M.D.G., J.L., K.D., Y.L., P.J.H.) and Analytical Sciences (W.L.), Janssen R&D LLC, Spring House, Pennsylvania; Cardiovascular and Metabolism Experimental and Translational Medicine, Janssen R&D LLC, San Diego, California (D.P.); and Alkek Center for Metagenomics and Microbiome Research, Department of Molecular Virology and Microbiology, Baylor College of Medicine, Houston, Texas (N.J.A.)
| | - Gee-Hong Kuo
- Cardiovascular and Metabolism Discovery (F.D., S.A.H., C.C., N.W., T.K., M.J., G.-H.K., M.D.G., J.L., K.D., Y.L., P.J.H.) and Analytical Sciences (W.L.), Janssen R&D LLC, Spring House, Pennsylvania; Cardiovascular and Metabolism Experimental and Translational Medicine, Janssen R&D LLC, San Diego, California (D.P.); and Alkek Center for Metagenomics and Microbiome Research, Department of Molecular Virology and Microbiology, Baylor College of Medicine, Houston, Texas (N.J.A.)
| | - Micheal D Gaul
- Cardiovascular and Metabolism Discovery (F.D., S.A.H., C.C., N.W., T.K., M.J., G.-H.K., M.D.G., J.L., K.D., Y.L., P.J.H.) and Analytical Sciences (W.L.), Janssen R&D LLC, Spring House, Pennsylvania; Cardiovascular and Metabolism Experimental and Translational Medicine, Janssen R&D LLC, San Diego, California (D.P.); and Alkek Center for Metagenomics and Microbiome Research, Department of Molecular Virology and Microbiology, Baylor College of Medicine, Houston, Texas (N.J.A.)
| | - James Lenhard
- Cardiovascular and Metabolism Discovery (F.D., S.A.H., C.C., N.W., T.K., M.J., G.-H.K., M.D.G., J.L., K.D., Y.L., P.J.H.) and Analytical Sciences (W.L.), Janssen R&D LLC, Spring House, Pennsylvania; Cardiovascular and Metabolism Experimental and Translational Medicine, Janssen R&D LLC, San Diego, California (D.P.); and Alkek Center for Metagenomics and Microbiome Research, Department of Molecular Virology and Microbiology, Baylor College of Medicine, Houston, Texas (N.J.A.)
| | - Keith Demarest
- Cardiovascular and Metabolism Discovery (F.D., S.A.H., C.C., N.W., T.K., M.J., G.-H.K., M.D.G., J.L., K.D., Y.L., P.J.H.) and Analytical Sciences (W.L.), Janssen R&D LLC, Spring House, Pennsylvania; Cardiovascular and Metabolism Experimental and Translational Medicine, Janssen R&D LLC, San Diego, California (D.P.); and Alkek Center for Metagenomics and Microbiome Research, Department of Molecular Virology and Microbiology, Baylor College of Medicine, Houston, Texas (N.J.A.)
| | - Nadim J Ajami
- Cardiovascular and Metabolism Discovery (F.D., S.A.H., C.C., N.W., T.K., M.J., G.-H.K., M.D.G., J.L., K.D., Y.L., P.J.H.) and Analytical Sciences (W.L.), Janssen R&D LLC, Spring House, Pennsylvania; Cardiovascular and Metabolism Experimental and Translational Medicine, Janssen R&D LLC, San Diego, California (D.P.); and Alkek Center for Metagenomics and Microbiome Research, Department of Molecular Virology and Microbiology, Baylor College of Medicine, Houston, Texas (N.J.A.)
| | - Yin Liang
- Cardiovascular and Metabolism Discovery (F.D., S.A.H., C.C., N.W., T.K., M.J., G.-H.K., M.D.G., J.L., K.D., Y.L., P.J.H.) and Analytical Sciences (W.L.), Janssen R&D LLC, Spring House, Pennsylvania; Cardiovascular and Metabolism Experimental and Translational Medicine, Janssen R&D LLC, San Diego, California (D.P.); and Alkek Center for Metagenomics and Microbiome Research, Department of Molecular Virology and Microbiology, Baylor College of Medicine, Houston, Texas (N.J.A.)
| | - Pamela J Hornby
- Cardiovascular and Metabolism Discovery (F.D., S.A.H., C.C., N.W., T.K., M.J., G.-H.K., M.D.G., J.L., K.D., Y.L., P.J.H.) and Analytical Sciences (W.L.), Janssen R&D LLC, Spring House, Pennsylvania; Cardiovascular and Metabolism Experimental and Translational Medicine, Janssen R&D LLC, San Diego, California (D.P.); and Alkek Center for Metagenomics and Microbiome Research, Department of Molecular Virology and Microbiology, Baylor College of Medicine, Houston, Texas (N.J.A.)
| |
Collapse
|
|
38
|
Mühlemann M, Zdzieblo D, Friedrich A, Berger C, Otto C, Walles H, Koepsell H, Metzger M. Altered pancreatic islet morphology and function in SGLT1 knockout mice on a glucose-deficient, fat-enriched diet. Mol Metab 2018; 13:67-76. [PMID: 29859847 PMCID: PMC6026318 DOI: 10.1016/j.molmet.2018.05.011] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/20/2018] [Revised: 05/08/2018] [Accepted: 05/15/2018] [Indexed: 12/13/2022] Open
Abstract
OBJECTIVES Glycemic control by medical treatment represents one therapeutic strategy for diabetic patients. The Na+-d-glucose cotransporter 1 (SGLT1) is currently of high interest in this context. SGLT1 is known to mediate glucose absorption and incretin secretion in the small intestine. Recently, inhibition of SGLT1 function was shown to improve postprandial hyperglycemia. In view of the lately demonstrated SGLT1 expression in pancreatic islets, we investigated if loss of SGLT1 affects islet morphology and function. METHODS Effects associated with the loss of SGLT1 on pancreatic islet (cyto) morphology and function were investigated by analyzing islets of a SGLT1 knockout mouse model, that were fed a glucose-deficient, fat-enriched diet (SGLT1-/--GDFE) to circumvent the glucose-galactose malabsorption syndrome. To distinguish diet- and Sglt1-/--dependent effects, wildtype mice on either standard chow (WT-SC) or the glucose-free, fat-enriched diet (WT-GDFE) were used as controls. Feeding a glucose-deficient, fat-enriched diet further required the analysis of intestinal SGLT1 expression and function under diet-conditions. RESULTS Consistent with literature, our data provide evidence that small intestinal SGLT1 mRNA expression and function is regulated by nutrition. In contrast, pancreatic SGLT1 mRNA levels were not affected by the applied diet, suggesting different regulatory mechanisms for SGLT1 in diverse tissues. Morphological changes such as increased islet sizes and cell numbers associated with changes in proliferation and apoptosis and alterations of the β- and α-cell population are specifically observed for pancreatic islets of SGLT1-/--GDFE mice. Glucose stimulation revealed no insulin response in SGLT1-/--GDFE mice while WT-GDFE mice displayed only a minor increase of blood insulin. Irregular glucagon responses were observed for both, SGLT1-/--GDFE and WT-GDFE mice. Further, both animal groups showed a sustained release of GLP-1 compared to WT-SC controls. CONCLUSION Loss or impairment of SGLT1 results in abnormal pancreatic islet (cyto)morphology and disturbed islet function regarding the insulin or glucagon release capacity from β- or α-cells, respectively. Consequently, our findings propose a new, additional role for SGLT1 maintaining proper islet structure and function.
Collapse
Affiliation(s)
- Markus Mühlemann
- Chair Tissue Engineering and Regenerative Medicine, University Hospital Würzburg, 97070, Würzburg, Germany
| | - Daniela Zdzieblo
- Chair Tissue Engineering and Regenerative Medicine, University Hospital Würzburg, 97070, Würzburg, Germany.
| | - Alexandra Friedrich
- Department of Molecular Plant Physiology and Biophysics, Julius-von-Sachs-Institute, University of Würzburg, 97070, Würzburg, Germany
| | - Constantin Berger
- Chair Tissue Engineering and Regenerative Medicine, University Hospital Würzburg, 97070, Würzburg, Germany
| | - Christoph Otto
- Department of General Visceral Vascular and Pediatric Surgery, University Hospital Würzburg, 97070, Würzburg, Germany
| | - Heike Walles
- Chair Tissue Engineering and Regenerative Medicine, University Hospital Würzburg, 97070, Würzburg, Germany; Translational Center Regenerative Therapies (TLC-RT), Fraunhofer Institute for Silicate Research ISC, 97070, Würzburg, Germany
| | - Hermann Koepsell
- Department of Molecular Plant Physiology and Biophysics, Julius-von-Sachs-Institute, University of Würzburg, 97070, Würzburg, Germany
| | - Marco Metzger
- Chair Tissue Engineering and Regenerative Medicine, University Hospital Würzburg, 97070, Würzburg, Germany; Translational Center Regenerative Therapies (TLC-RT), Fraunhofer Institute for Silicate Research ISC, 97070, Würzburg, Germany
| |
Collapse
|
|
39
|
Ohno H, Kojima Y, Harada H, Abe Y, Endo T, Kobayashi M. Absorption, disposition, metabolism and excretion of [ 14C]mizagliflozin, a novel selective SGLT1 inhibitor, in rats. Xenobiotica 2018; 49:463-473. [PMID: 29558223 DOI: 10.1080/00498254.2018.1449269] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
The pharmacokinetic and metabolite profiles of mizagliflozin, a novel selective sodium glucose co-transporter 1 inhibitor designed to act only in the intestine, were investigated in rats. Mizagliflozin administrated intravenously (0.3 mg/kg) and orally (3 mg/kg) declined with a short half-life (0.23 and 1.14 h, respectively). The absolute bioavailability was only 0.02%. Following intravenous administration of [14 C]mizagliflozin (0.3 mg/kg), radioactivity in plasma was also rapidly declined. Up to 24 h after oral administration of [14 C]mizagliflozin (1 mg/kg), radioactivity was recovered in the faeces (98.4%) and in the urine (0.8%). No remarkable accumulation of radioactivity in tissues was observed using tissue dissection technique and whole body autoradiography. Orally dosed [14 C]mizagliflozin was mostly metabolised to its aglycone, KP232, in the intestine. In the plasma, KP232 and its glucuronide were predominant. KP232 glucuronide was also prominent in the bile and was recovered as KP232 in the faeces possibly because of the deconjugation by gut microflora. Mizagliflozin was observed neither in the urine nor the faeces. These findings suggest that orally administered mizagliflozin is poorly absorbed, contributing to low systemic exposure; if absorbed, mizagliflozin is rapidly cleared from circulation.
Collapse
Affiliation(s)
- Hitoshi Ohno
- a Central Research Laboratories , Kissei Pharmaceutical Co., Ltd , Azumino , Japan
| | - Yasunari Kojima
- a Central Research Laboratories , Kissei Pharmaceutical Co., Ltd , Azumino , Japan
| | - Hiroshi Harada
- a Central Research Laboratories , Kissei Pharmaceutical Co., Ltd , Azumino , Japan
| | - Yoshikazu Abe
- a Central Research Laboratories , Kissei Pharmaceutical Co., Ltd , Azumino , Japan
| | - Takuro Endo
- a Central Research Laboratories , Kissei Pharmaceutical Co., Ltd , Azumino , Japan
| | - Mamoru Kobayashi
- a Central Research Laboratories , Kissei Pharmaceutical Co., Ltd , Azumino , Japan
| |
Collapse
|
|
40
|
Wright EM, Ghezzi C, Loo DDF. Novel and Unexpected Functions of SGLTs. Physiology (Bethesda) 2017; 32:435-443. [PMID: 29021363 PMCID: PMC5817162 DOI: 10.1152/physiol.00021.2017] [Citation(s) in RCA: 47] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2017] [Revised: 08/25/2017] [Accepted: 08/25/2017] [Indexed: 12/13/2022] Open
Abstract
It has been 30 years since the intestinal sodium glucose cotransporter SGLT1 was cloned, and, in the intervening years, there have been many advances that have influenced physiology and medicine. Among the first was that SGLT1 is the founding member of the human gene family SLC5, containing 11 diverse transporters and a glucose sensor. Equally surprising was that SGLTs are members of a structural family of cotransporters and exchangers in different gene families. This led to the conclusion that these proteins operate by a mechanism where transport involves the opening and closing of external and internal gates. The mechanism is shared by a wide variety of transporters in different structural families, e.g., the human facilitated glucose transporters (SLC2) in the huge major facilitator superfamily (MFS). Not surprising is the finding that mutations in Sglt genes cause the rare diseases glucose-galactose-malabsorption (GGM) and familial renal glucosuria (FRG). However, it was not envisaged that SGLT inhibitors would be used to treat diabetes mellitus, and these drugs may be able to treat cancer. Finally, in 2017, we have just learned that SGLT1 may be required to resist infection and to avoid recurrent pregnancy loss.
Collapse
Affiliation(s)
- Ernest M Wright
- Department of Physiology, David Geffen School of Medicine at UCLA, Los Angeles, California
| | - Chiara Ghezzi
- Department of Physiology, David Geffen School of Medicine at UCLA, Los Angeles, California
| | - Donald D F Loo
- Department of Physiology, David Geffen School of Medicine at UCLA, Los Angeles, California
| |
Collapse
|
|
41
|
Mizagliflozin, a novel selective SGLT1 inhibitor, exhibits potential in the amelioration of chronic constipation. Eur J Pharmacol 2017; 806:25-31. [DOI: 10.1016/j.ejphar.2017.04.010] [Citation(s) in RCA: 36] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2016] [Revised: 04/10/2017] [Accepted: 04/10/2017] [Indexed: 12/13/2022]
|
|
42
|
Powell DR, Smith MG, Doree DD, Harris AL, Greer J, DaCosta CM, Thompson A, Jeter-Jones S, Xiong W, Carson KG, Goodwin NC, Harrison BA, Rawlins DB, Strobel ED, Gopinathan S, Wilson A, Mseeh F, Zambrowicz B, Ding ZM. LX2761, a Sodium/Glucose Cotransporter 1 Inhibitor Restricted to the Intestine, Improves Glycemic Control in Mice. J Pharmacol Exp Ther 2017; 362:85-97. [PMID: 28442582 DOI: 10.1124/jpet.117.240820] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2017] [Accepted: 04/20/2017] [Indexed: 12/15/2022] Open
Abstract
LX2761 is a potent sodium/glucose cotransporter 1 inhibitor restricted to the intestinal lumen after oral administration. Studies presented here evaluated the effect of orally administered LX2761 on glycemic control in preclinical models. In healthy mice and rats treated with LX2761, blood glucose excursions were lower and plasma total glucagon-like peptide-1 (GLP-1) levels higher after an oral glucose challenge; these decreased glucose excursions persisted even when the glucose challenge occurred 15 hours after LX2761 dosing in ad lib-fed mice. Further, treating mice with LX2761 and the dipeptidyl-peptidase 4 inhibitor sitagliptin synergistically increased active GLP-1 levels, suggesting increased LX2761-mediated release of GLP-1 into the portal circulation. LX2761 also lowered postprandial glucose, fasting glucose, and hemoglobin A1C, and increased plasma total GLP-1, during long-term treatment of mice with either early- or late-onset streptozotocin-diabetes; in the late-onset cohort, LX2761 treatment improved survival. Mice and rats treated with LX2761 occasionally had diarrhea; this dose-dependent side effect decreased in severity and frequency over time, and LX2761 doses were identified that decreased postprandial glucose excursions without causing diarrhea. Further, the frequency of LX2761-associated diarrhea was greatly decreased in mice either by gradual dose escalation or by pretreatment with resistant starch 4, which is slowly digested to glucose in the colon, a process that primes the colon for glucose metabolism by selecting for glucose-fermenting bacterial species. These data suggest that clinical trials are warranted to determine if LX2761 doses and dosing strategies exist that provide improved glycemic control combined with adequate gastrointestinal tolerability in people living with diabetes.
Collapse
Affiliation(s)
| | | | - Deon D Doree
- Lexicon Pharmaceuticals, Inc., The Woodlands, Texas
| | | | | | | | | | | | - Wendy Xiong
- Lexicon Pharmaceuticals, Inc., The Woodlands, Texas
| | | | | | | | | | | | | | - Alan Wilson
- Lexicon Pharmaceuticals, Inc., The Woodlands, Texas
| | - Faika Mseeh
- Lexicon Pharmaceuticals, Inc., The Woodlands, Texas
| | | | | |
Collapse
|
|
43
|
The Na+-D-glucose cotransporters SGLT1 and SGLT2 are targets for the treatment of diabetes and cancer. Pharmacol Ther 2017; 170:148-165. [DOI: 10.1016/j.pharmthera.2016.10.017] [Citation(s) in RCA: 106] [Impact Index Per Article: 13.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
|
|
44
|
Jesus AR, Vila-Viçosa D, Machuqueiro M, Marques AP, Dore TM, Rauter AP. Targeting Type 2 Diabetes with C-Glucosyl Dihydrochalcones as Selective Sodium Glucose Co-Transporter 2 (SGLT2) Inhibitors: Synthesis and Biological Evaluation. J Med Chem 2017; 60:568-579. [DOI: 10.1021/acs.jmedchem.6b01134] [Citation(s) in RCA: 42] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022]
Affiliation(s)
- Ana R. Jesus
- Centro
de Química e Bioquímica, Faculdade de Ciências, Universidade de Lisboa, Ed C8, Piso 5, Campo Grande, 1749-016 Lisboa, Portugal
- New York University Abu Dhabi, P.O. Box 129188, Abu Dhabi, United Arab Emirates
| | - Diogo Vila-Viçosa
- Centro
de Química e Bioquímica, Faculdade de Ciências, Universidade de Lisboa, Ed C8, Piso 5, Campo Grande, 1749-016 Lisboa, Portugal
| | - Miguel Machuqueiro
- Centro
de Química e Bioquímica, Faculdade de Ciências, Universidade de Lisboa, Ed C8, Piso 5, Campo Grande, 1749-016 Lisboa, Portugal
| | - Ana P. Marques
- Centro
de Química e Bioquímica, Faculdade de Ciências, Universidade de Lisboa, Ed C8, Piso 5, Campo Grande, 1749-016 Lisboa, Portugal
| | - Timothy M. Dore
- New York University Abu Dhabi, P.O. Box 129188, Abu Dhabi, United Arab Emirates
| | - Amélia P. Rauter
- Centro
de Química e Bioquímica, Faculdade de Ciências, Universidade de Lisboa, Ed C8, Piso 5, Campo Grande, 1749-016 Lisboa, Portugal
| |
Collapse
|
|
45
|
Goodwin NC, Ding ZM, Harrison BA, Strobel ED, Harris AL, Smith M, Thompson AY, Xiong W, Mseeh F, Bruce DJ, Diaz D, Gopinathan S, Li L, O'Neill E, Thiel M, Wilson AGE, Carson KG, Powell DR, Rawlins DB. Discovery of LX2761, a Sodium-Dependent Glucose Cotransporter 1 (SGLT1) Inhibitor Restricted to the Intestinal Lumen, for the Treatment of Diabetes. J Med Chem 2017; 60:710-721. [PMID: 28045524 DOI: 10.1021/acs.jmedchem.6b01541] [Citation(s) in RCA: 50] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/10/2023]
Abstract
The increasing number of people afflicted with diabetes throughout the world is a major health issue. Inhibitors of the sodium-dependent glucose cotransporters (SGLT) have appeared as viable therapeutics to control blood glucose levels in diabetic patents. Herein we report the discovery of LX2761, a locally acting SGLT1 inhibitor that is highly potent in vitro and delays intestinal glucose absorption in vivo to improve glycemic control.
Collapse
Affiliation(s)
- Nicole C Goodwin
- Department of Medicinal Chemistry, Lexicon Pharmaceuticals , 110 Allen Road, Basking Ridge, New Jersey 07920, United States
| | | | - Bryce A Harrison
- Department of Medicinal Chemistry, Lexicon Pharmaceuticals , 110 Allen Road, Basking Ridge, New Jersey 07920, United States
| | - Eric D Strobel
- Department of Medicinal Chemistry, Lexicon Pharmaceuticals , 110 Allen Road, Basking Ridge, New Jersey 07920, United States
| | | | | | | | | | | | | | | | | | | | | | | | | | - Kenneth G Carson
- Department of Medicinal Chemistry, Lexicon Pharmaceuticals , 110 Allen Road, Basking Ridge, New Jersey 07920, United States
| | | | - David B Rawlins
- Department of Medicinal Chemistry, Lexicon Pharmaceuticals , 110 Allen Road, Basking Ridge, New Jersey 07920, United States
| |
Collapse
|
|
46
|
Lehmann A, Hornby PJ. Intestinal SGLT1 in metabolic health and disease. Am J Physiol Gastrointest Liver Physiol 2016; 310:G887-98. [PMID: 27012770 DOI: 10.1152/ajpgi.00068.2016] [Citation(s) in RCA: 67] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/15/2016] [Accepted: 03/21/2016] [Indexed: 01/31/2023]
Abstract
The Na(+)-glucose cotransporter 1 (SGLT1/SLC5A1) is predominantly expressed in the small intestine. It transports glucose and galactose across the apical membrane in a process driven by a Na(+) gradient created by Na(+)-K(+)-ATPase. SGLT2 is the major form found in the kidney, and SGLT2-selective inhibitors are a new class of treatment for type 2 diabetes mellitus (T2DM). Recent data from patients treated with dual SGLT1/2 inhibitors or SGLT2-selective drugs such as canagliflozin (SGLT1 IC50 = 663 nM) warrant evaluation of SGLT1 inhibition for T2DM. SGLT1 activity is highly dynamic, with modulation by multiple mechanisms to ensure maximal uptake of carbohydrates (CHOs). Intestinal SGLT1 inhibition lowers and delays the glucose excursion following CHO ingestion and augments glucagon-like peptide-1 (GLP-1) and peptide YY (PYY) secretion. The latter is likely due to increased glucose exposure of the colonic microbiota and formation of metabolites such as L cell secretagogues. GLP-1 and PYY secretion suppresses food intake, enhances the ileal brake, and has an incretin effect. An increase in colonic microbial production of propionate could contribute to intestinal gluconeogenesis and mediate positive metabolic effects. On the other hand, a threshold of SGLT1 inhibition that could lead to gastrointestinal intolerability is unclear. Altered Na(+) homeostasis and increased colonic CHO may result in diarrhea and adverse gastrointestinal effects. This review considers the potential mechanisms contributing to positive metabolic and negative intestinal effects. Compounds that inhibit SGLT1 must balance the modulation of these mechanisms to achieve therapeutic efficacy for metabolic diseases.
Collapse
Affiliation(s)
- Anders Lehmann
- Division of Endocrinology, Department of Physiology, Institute of Neuroscience and Physiology, Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden; and
| | - Pamela J Hornby
- Cardiovascular and Metabolic Disease, Janssen Research and Development, LLC, Spring House, Pennsylvania
| |
Collapse
|
|
47
|
Abstract
PURPOSE OF REVIEW Sodium-glucose cotransporters (SGLTs) are important mediators of glucose uptake across apical cell membranes. SGLT1 mediates almost all sodium-dependent glucose uptake in the small intestine, while in the kidney SGLT2, and to a lesser extent SGLT1, account for more than 90% and nearly 3%, respectively, of glucose reabsorption from the glomerular ultrafiltrate. Although the recent availability of SGLT2 inhibitors for the treatment of diabetes mellitus has increased the number of clinical studies, this review has a focus on mechanisms contributing to the cellular regulation of SGLTs. RECENT FINDINGS Studies have focused on the regulation of SGLT expression under different physiological/pathophysiological conditions, for example diet, age or diabetes mellitus. Several studies provide evidence of SGLT regulation via cyclic adenosine monophosphate/protein kinase A, protein kinase C, glucagon-like peptide 2, insulin, leptin, signal transducer and activator of transcription-3 (STAT3), phosphoinositide-3 kinase (PI3K)/Akt, mitogen-activated protein kinases (MAPKs), nuclear factor-kappaB (NF-kappaB), with-no-K[Lys] kinases/STE20/SPS1-related proline/alanine-rich kinase (Wnk/SPAK) and regulatory solute carrier protein 1 (RS1) pathways. SUMMARY SGLT inhibitors are important drugs for glycemic control in diabetes mellitus. Although the contribution of SGLT1 for absorption of glucose from the intestine as well as SGLT2/SGLT1 for renal glucose reabsorption has been comprehensively defined, this review provides an up-to-date outline for the mechanistic regulation of SGLT1/SGLT2.
Collapse
|
|
48
|
Song P, Onishi A, Koepsell H, Vallon V. Sodium glucose cotransporter SGLT1 as a therapeutic target in diabetes mellitus. Expert Opin Ther Targets 2016; 20:1109-25. [PMID: 26998950 DOI: 10.1517/14728222.2016.1168808] [Citation(s) in RCA: 137] [Impact Index Per Article: 15.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
INTRODUCTION Glycemic control is important in diabetes mellitus to minimize the progression of the disease and the risk of potentially devastating complications. Inhibition of the sodium-glucose cotransporter SGLT2 induces glucosuria and has been established as a new anti-hyperglycemic strategy. SGLT1 plays a distinct and complementing role to SGLT2 in glucose homeostasis and, therefore, SGLT1 inhibition may also have therapeutic potential. AREAS COVERED This review focuses on the physiology of SGLT1 in the small intestine and kidney and its pathophysiological role in diabetes. The therapeutic potential of SGLT1 inhibition, alone as well as in combination with SGLT2 inhibition, for anti-hyperglycemic therapy are discussed. Additionally, this review considers the effects on other SGLT1-expressing organs like the heart. EXPERT OPINION SGLT1 inhibition improves glucose homeostasis by reducing dietary glucose absorption in the intestine and by increasing the release of gastrointestinal incretins like glucagon-like peptide-1. SGLT1 inhibition has a small glucosuric effect in the normal kidney and this effect is increased in diabetes and during inhibition of SGLT2, which deliver more glucose to SGLT1 in late proximal tubule. In short-term studies, inhibition of SGLT1 and combined SGLT1/SGLT2 inhibition appeared to be safe. More data is needed on long-term safety and cardiovascular consequences of SGLT1 inhibition.
Collapse
Affiliation(s)
- Panai Song
- a Division of Nephrology & Hypertension, Department of Medicine , University of California San Diego , La Jolla , CA , USA.,b VA San Diego Healthcare System , San Diego , CA , USA.,c Department of Nephrology, Second Xiangya Hospital , Central South University , Changsha , China
| | - Akira Onishi
- a Division of Nephrology & Hypertension, Department of Medicine , University of California San Diego , La Jolla , CA , USA.,b VA San Diego Healthcare System , San Diego , CA , USA.,d Division of Nephrology, Department of Medicine , Jichi Medical University , Shimotsuke , Japan
| | - Hermann Koepsell
- e Department of Molecular Plant Physiology and Biophysics, Julius-von-Sachs-Institute , University of Würzburg , Würzburg , Germany
| | - Volker Vallon
- a Division of Nephrology & Hypertension, Department of Medicine , University of California San Diego , La Jolla , CA , USA.,b VA San Diego Healthcare System , San Diego , CA , USA.,f Department of Pharmacology , University of California San Diego , La Jolla , CA , USA
| |
Collapse
|
|
49
|
Estudante M, Soveral G, Morais JG, Benet LZ. Insights into solute carriers: physiological functions and implications in disease and pharmacokinetics. MEDCHEMCOMM 2016. [DOI: 10.1039/c6md00188b] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
SLCs transport many endogenous and exogenous compounds including drugs; SLCs dysfunction has implications in pharmacokinetics, drug toxicity or lack of efficacy.
Collapse
Affiliation(s)
- Margarida Estudante
- Department of Pharmacological Sciences
- Faculty of Pharmacy
- Universidade de Lisboa
- Portugal
- Research Institute for Medicines (iMed.ULisboa)
| | - Graça Soveral
- Research Institute for Medicines (iMed.ULisboa)
- Faculty of Pharmacy
- Universidade de Lisboa
- Portugal
| | - José G. Morais
- Department of Pharmacological Sciences
- Faculty of Pharmacy
- Universidade de Lisboa
- Portugal
- Research Institute for Medicines (iMed.ULisboa)
| | - Leslie Z. Benet
- Department of Bioengineering and Therapeutic Sciences
- University of California
- San Francisco
- USA
| |
Collapse
|
|
50
|
Huard K, Brown J, Jones JC, Cabral S, Futatsugi K, Gorgoglione M, Lanba A, Vera NB, Zhu Y, Yan Q, Zhou Y, Vernochet C, Riccardi K, Wolford A, Pirman D, Niosi M, Aspnes G, Herr M, Genung NE, Magee TV, Uccello DP, Loria P, Di L, Gosset JR, Hepworth D, Rolph T, Pfefferkorn JA, Erion DM. Discovery and characterization of novel inhibitors of the sodium-coupled citrate transporter (NaCT or SLC13A5). Sci Rep 2015; 5:17391. [PMID: 26620127 PMCID: PMC4664966 DOI: 10.1038/srep17391] [Citation(s) in RCA: 55] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2015] [Accepted: 10/29/2015] [Indexed: 12/13/2022] Open
Abstract
Citrate is a key regulatory metabolic intermediate as it facilitates the integration of the glycolysis and lipid synthesis pathways. Inhibition of hepatic extracellular citrate uptake, by blocking the sodium-coupled citrate transporter (NaCT or SLC13A5), has been suggested as a potential therapeutic approach to treat metabolic disorders. NaCT transports citrate from the blood into the cell coupled to the transport of sodium ions. The studies herein report the identification and characterization of a novel small dicarboxylate molecule (compound 2) capable of selectively and potently inhibiting citrate transport through NaCT, both in vitro and in vivo. Binding and transport experiments indicate that 2 specifically binds NaCT in a competitive and stereosensitive manner, and is recognized as a substrate for transport by NaCT. The favorable pharmacokinetic properties of 2 permitted in vivo experiments to evaluate the effect of inhibiting hepatic citrate uptake on metabolic endpoints.
Collapse
Affiliation(s)
- Kim Huard
- Worldwide Medicinal Chemistry, 610 Main street, Cambridge, MA 02139
| | - Janice Brown
- Pharmacokinetics, Dynamics, and Metabolism, Eastern Point road, Groton, CT 06340
| | - Jessica C Jones
- Cardiovascular, Metabolic &Endocrine Disease Research Unit, 610 Main street, Cambridge, MA 02139
| | - Shawn Cabral
- Worldwide Medicinal Chemistry, Eastern Point road, Groton, CT 06340
| | | | - Matthew Gorgoglione
- Cardiovascular, Metabolic &Endocrine Disease Research Unit, 610 Main street, Cambridge, MA 02139
| | - Adhiraj Lanba
- Cardiovascular, Metabolic &Endocrine Disease Research Unit, 610 Main street, Cambridge, MA 02139
| | - Nicholas B Vera
- Cardiovascular, Metabolic &Endocrine Disease Research Unit, 610 Main street, Cambridge, MA 02139
| | - Yimin Zhu
- Cardiovascular, Metabolic &Endocrine Disease Research Unit, 610 Main street, Cambridge, MA 02139
| | - Qingyun Yan
- Cardiovascular, Metabolic &Endocrine Disease Research Unit, 610 Main street, Cambridge, MA 02139
| | - Yingjiang Zhou
- Cardiovascular, Metabolic &Endocrine Disease Research Unit, 610 Main street, Cambridge, MA 02139
| | - Cecile Vernochet
- Cardiovascular, Metabolic &Endocrine Disease Research Unit, 610 Main street, Cambridge, MA 02139
| | - Keith Riccardi
- Pharmacokinetics, Dynamics, and Metabolism, Eastern Point road, Groton, CT 06340
| | - Angela Wolford
- Pharmacokinetics, Dynamics, and Metabolism, Eastern Point road, Groton, CT 06340
| | - David Pirman
- Pharmacokinetics, Dynamics, and Metabolism, Eastern Point road, Groton, CT 06340
| | - Mark Niosi
- Pharmacokinetics, Dynamics, and Metabolism, Eastern Point road, Groton, CT 06340
| | - Gary Aspnes
- Worldwide Medicinal Chemistry, 610 Main street, Cambridge, MA 02139
| | - Michael Herr
- Worldwide Medicinal Chemistry, Eastern Point road, Groton, CT 06340
| | - Nathan E Genung
- Worldwide Medicinal Chemistry, Eastern Point road, Groton, CT 06340
| | - Thomas V Magee
- Worldwide Medicinal Chemistry, 610 Main street, Cambridge, MA 02139
| | - Daniel P Uccello
- Worldwide Medicinal Chemistry, Eastern Point road, Groton, CT 06340
| | - Paula Loria
- Pharmacokinetics, Dynamics, and Metabolism, Eastern Point road, Groton, CT 06340
| | - Li Di
- Pharmacokinetics, Dynamics, and Metabolism, Eastern Point road, Groton, CT 06340
| | - James R Gosset
- Pharmacokinetics, Dynamics, and Metabolism, 610 Main street, Cambridge, MA 02139
| | - David Hepworth
- Worldwide Medicinal Chemistry, 610 Main street, Cambridge, MA 02139
| | - Timothy Rolph
- Cardiovascular, Metabolic &Endocrine Disease Research Unit, 610 Main street, Cambridge, MA 02139
| | - Jeffrey A Pfefferkorn
- Cardiovascular, Metabolic &Endocrine Disease Research Unit, 610 Main street, Cambridge, MA 02139
| | - Derek M Erion
- Cardiovascular, Metabolic &Endocrine Disease Research Unit, 610 Main street, Cambridge, MA 02139
| |
Collapse
|