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Development of SGLT1 and SGLT2 inhibitors

Sodium–glucose cotransporters SGLT1 (encoded by SGLT1 , also known as SLC5A1 ) and SGLT2 (encoded by SGLT2 , also known as SLC5A2 ) are important mediators of epithelial glucose transport. While SGLT1 accounts for most of the dietary glucose uptake in the intestine, SGLT2 is responsible for the majo... Full description

Journal Title: Diabetologia 2018, Vol.61 (10), p.2079-2086
Main Author: Rieg, Timo
Other Authors: Vallon, Volker
Format: Electronic Article Electronic Article
Language: English
Subjects:
Publisher: Berlin/Heidelberg: Springer Berlin Heidelberg
ID: ISSN: 0012-186X
Link: https://www.ncbi.nlm.nih.gov/pubmed/30132033
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recordid: cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_6124499
title: Development of SGLT1 and SGLT2 inhibitors
format: Article
creator:
  • Rieg, Timo
  • Vallon, Volker
subjects:
  • Analysis
  • Animal models
  • Animals
  • Article
  • Blood Glucose - metabolism
  • Cardiovascular system
  • Chronic kidney disease
  • Chronic kidney failure
  • Cloning
  • Dextrose
  • Diabetes mellitus
  • Diabetes mellitus (non-insulin dependent)
  • Diabetes Mellitus, Type 1 - drug therapy
  • Diabetes Mellitus, Type 1 - metabolism
  • Diabetes Mellitus, Type 2 - drug therapy
  • Diabetes Mellitus, Type 2 - metabolism
  • Diabetic Ketoacidosis - prevention & control
  • digestive
  • Disease Models, Animal
  • Drug approval
  • Drug Design
  • Drug development
  • Drug discovery
  • Galactose
  • Genetically modified organisms
  • Glucose
  • Glucose - metabolism
  • Glucose transport
  • Heart diseases
  • Heart failure
  • Human Physiology
  • Humans
  • Inhibitor
  • Internal Medicine
  • Intestinal glucose transport
  • Intestinal Mucosa - metabolism
  • Intestine
  • Kidney - metabolism
  • Kidneys
  • Malabsorption
  • Mathematical models
  • Medicine
  • Medicine & Public Health
  • Metabolic Diseases
  • Mice
  • Mutation
  • oral
  • Phlorhizin - pharmacology
  • Renal failure
  • Renal glucose transport
  • Review
  • skin physiology
  • Sodium
  • Sodium-Glucose Transporter 1 - antagonists & inhibitors
  • Sodium-Glucose Transporter 2 - metabolism
  • Sodium-Glucose Transporter 2 Inhibitors - pharmacology
  • Sodium–glucose cotransporter
  • Type 1 diabetes
  • Type 2 diabetes
ispartof: Diabetologia, 2018, Vol.61 (10), p.2079-2086
description: Sodium–glucose cotransporters SGLT1 (encoded by SGLT1 , also known as SLC5A1 ) and SGLT2 (encoded by SGLT2 , also known as SLC5A2 ) are important mediators of epithelial glucose transport. While SGLT1 accounts for most of the dietary glucose uptake in the intestine, SGLT2 is responsible for the majority of glucose reuptake in the tubular system of the kidney, with SGLT1 reabsorbing the remainder of the filtered glucose. As a consequence, mutations in the SLC5A1 gene cause glucose/galactose malabsorption, whereas mutations in SLC5A2 are associated with glucosuria. Since the cloning of SGLT1 more than 30 years ago, big strides have been made in our understanding of these transporters and their suitability as drug targets. Phlorizin, a naturally occurring competitive inhibitor of SGLT1 and SGLT2, provided the first insights into potential efficacy, but its use was hampered by intestinal side effects and a short half-life. Nevertheless, it was a starting point for the development of specific inhibitors of SGLT1 and SGLT2, as well as dual SGLT1/2 inhibitors. Since the approval of the first SGLT2 inhibitor in 2013 by the US Food and Drug Administration, SGLT2 inhibitors have become a new mainstay in the treatment of type 2 diabetes mellitus. They also have beneficial effects on the cardiovascular system (including heart failure) and the kidney. This review focuses on the rationale for the development of individual SGLT2 and SGLT1 inhibitors, as well as dual SGLT1/2 inhibition, including, but not limited to, aspects of genetics, genetically modified mouse models, mathematical modelling and general considerations of drug discovery in the field of metabolism.
language: eng
source:
identifier: ISSN: 0012-186X
fulltext: no_fulltext
issn:
  • 0012-186X
  • 1432-0428
url: Link


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descriptionSodium–glucose cotransporters SGLT1 (encoded by SGLT1 , also known as SLC5A1 ) and SGLT2 (encoded by SGLT2 , also known as SLC5A2 ) are important mediators of epithelial glucose transport. While SGLT1 accounts for most of the dietary glucose uptake in the intestine, SGLT2 is responsible for the majority of glucose reuptake in the tubular system of the kidney, with SGLT1 reabsorbing the remainder of the filtered glucose. As a consequence, mutations in the SLC5A1 gene cause glucose/galactose malabsorption, whereas mutations in SLC5A2 are associated with glucosuria. Since the cloning of SGLT1 more than 30 years ago, big strides have been made in our understanding of these transporters and their suitability as drug targets. Phlorizin, a naturally occurring competitive inhibitor of SGLT1 and SGLT2, provided the first insights into potential efficacy, but its use was hampered by intestinal side effects and a short half-life. Nevertheless, it was a starting point for the development of specific inhibitors of SGLT1 and SGLT2, as well as dual SGLT1/2 inhibitors. Since the approval of the first SGLT2 inhibitor in 2013 by the US Food and Drug Administration, SGLT2 inhibitors have become a new mainstay in the treatment of type 2 diabetes mellitus. They also have beneficial effects on the cardiovascular system (including heart failure) and the kidney. This review focuses on the rationale for the development of individual SGLT2 and SGLT1 inhibitors, as well as dual SGLT1/2 inhibition, including, but not limited to, aspects of genetics, genetically modified mouse models, mathematical modelling and general considerations of drug discovery in the field of metabolism.
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languageeng
publisherBerlin/Heidelberg: Springer Berlin Heidelberg
subjectAnalysis ; Animal models ; Animals ; Article ; Blood Glucose - metabolism ; Cardiovascular system ; Chronic kidney disease ; Chronic kidney failure ; Cloning ; Dextrose ; Diabetes mellitus ; Diabetes mellitus (non-insulin dependent) ; Diabetes Mellitus, Type 1 - drug therapy ; Diabetes Mellitus, Type 1 - metabolism ; Diabetes Mellitus, Type 2 - drug therapy ; Diabetes Mellitus, Type 2 - metabolism ; Diabetic Ketoacidosis - prevention & control ; digestive ; Disease Models, Animal ; Drug approval ; Drug Design ; Drug development ; Drug discovery ; Galactose ; Genetically modified organisms ; Glucose ; Glucose - metabolism ; Glucose transport ; Heart diseases ; Heart failure ; Human Physiology ; Humans ; Inhibitor ; Internal Medicine ; Intestinal glucose transport ; Intestinal Mucosa - metabolism ; Intestine ; Kidney - metabolism ; Kidneys ; Malabsorption ; Mathematical models ; Medicine ; Medicine & Public Health ; Metabolic Diseases ; Mice ; Mutation ; oral ; Phlorhizin - pharmacology ; Renal failure ; Renal glucose transport ; Review ; skin physiology ; Sodium ; Sodium-Glucose Transporter 1 - antagonists & inhibitors ; Sodium-Glucose Transporter 2 - metabolism ; Sodium-Glucose Transporter 2 Inhibitors - pharmacology ; Sodium–glucose cotransporter ; Type 1 diabetes ; Type 2 diabetes
ispartofDiabetologia, 2018, Vol.61 (10), p.2079-2086
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0Springer-Verlag GmbH Germany, part of Springer Nature 2018
1COPYRIGHT 2018 Springer
2Diabetologia is a copyright of Springer, (2018). All Rights Reserved.
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descriptionSodium–glucose cotransporters SGLT1 (encoded by SGLT1 , also known as SLC5A1 ) and SGLT2 (encoded by SGLT2 , also known as SLC5A2 ) are important mediators of epithelial glucose transport. While SGLT1 accounts for most of the dietary glucose uptake in the intestine, SGLT2 is responsible for the majority of glucose reuptake in the tubular system of the kidney, with SGLT1 reabsorbing the remainder of the filtered glucose. As a consequence, mutations in the SLC5A1 gene cause glucose/galactose malabsorption, whereas mutations in SLC5A2 are associated with glucosuria. Since the cloning of SGLT1 more than 30 years ago, big strides have been made in our understanding of these transporters and their suitability as drug targets. Phlorizin, a naturally occurring competitive inhibitor of SGLT1 and SGLT2, provided the first insights into potential efficacy, but its use was hampered by intestinal side effects and a short half-life. Nevertheless, it was a starting point for the development of specific inhibitors of SGLT1 and SGLT2, as well as dual SGLT1/2 inhibitors. Since the approval of the first SGLT2 inhibitor in 2013 by the US Food and Drug Administration, SGLT2 inhibitors have become a new mainstay in the treatment of type 2 diabetes mellitus. They also have beneficial effects on the cardiovascular system (including heart failure) and the kidney. This review focuses on the rationale for the development of individual SGLT2 and SGLT1 inhibitors, as well as dual SGLT1/2 inhibition, including, but not limited to, aspects of genetics, genetically modified mouse models, mathematical modelling and general considerations of drug discovery in the field of metabolism.
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0Analysis
1Animal models
2Animals
3Article
4Blood Glucose - metabolism
5Cardiovascular system
6Chronic kidney disease
7Chronic kidney failure
8Cloning
9Dextrose
10Diabetes mellitus
11Diabetes mellitus (non-insulin dependent)
12Diabetes Mellitus, Type 1 - drug therapy
13Diabetes Mellitus, Type 1 - metabolism
14Diabetes Mellitus, Type 2 - drug therapy
15Diabetes Mellitus, Type 2 - metabolism
16Diabetic Ketoacidosis - prevention & control
17digestive
18Disease Models, Animal
19Drug approval
20Drug Design
21Drug development
22Drug discovery
23Galactose
24Genetically modified organisms
25Glucose
26Glucose - metabolism
27Glucose transport
28Heart diseases
29Heart failure
30Human Physiology
31Humans
32Inhibitor
33Internal Medicine
34Intestinal glucose transport
35Intestinal Mucosa - metabolism
36Intestine
37Kidney - metabolism
38Kidneys
39Malabsorption
40Mathematical models
41Medicine
42Medicine & Public Health
43Metabolic Diseases
44Mice
45Mutation
46oral
47Phlorhizin - pharmacology
48Renal failure
49Renal glucose transport
50Review
51skin physiology
52Sodium
53Sodium-Glucose Transporter 1 - antagonists & inhibitors
54Sodium-Glucose Transporter 2 - metabolism
55Sodium-Glucose Transporter 2 Inhibitors - pharmacology
56Sodium–glucose cotransporter
57Type 1 diabetes
58Type 2 diabetes
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43Metabolic Diseases
44Mice
45Mutation
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47Phlorhizin - pharmacology
48Renal failure
49Renal glucose transport
50Review
51skin physiology
52Sodium
53Sodium-Glucose Transporter 1 - antagonists & inhibitors
54Sodium-Glucose Transporter 2 - metabolism
55Sodium-Glucose Transporter 2 Inhibitors - pharmacology
56Sodium–glucose cotransporter
57Type 1 diabetes
58Type 2 diabetes
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abstractSodium–glucose cotransporters SGLT1 (encoded by SGLT1 , also known as SLC5A1 ) and SGLT2 (encoded by SGLT2 , also known as SLC5A2 ) are important mediators of epithelial glucose transport. While SGLT1 accounts for most of the dietary glucose uptake in the intestine, SGLT2 is responsible for the majority of glucose reuptake in the tubular system of the kidney, with SGLT1 reabsorbing the remainder of the filtered glucose. As a consequence, mutations in the SLC5A1 gene cause glucose/galactose malabsorption, whereas mutations in SLC5A2 are associated with glucosuria. Since the cloning of SGLT1 more than 30 years ago, big strides have been made in our understanding of these transporters and their suitability as drug targets. Phlorizin, a naturally occurring competitive inhibitor of SGLT1 and SGLT2, provided the first insights into potential efficacy, but its use was hampered by intestinal side effects and a short half-life. Nevertheless, it was a starting point for the development of specific inhibitors of SGLT1 and SGLT2, as well as dual SGLT1/2 inhibitors. Since the approval of the first SGLT2 inhibitor in 2013 by the US Food and Drug Administration, SGLT2 inhibitors have become a new mainstay in the treatment of type 2 diabetes mellitus. They also have beneficial effects on the cardiovascular system (including heart failure) and the kidney. This review focuses on the rationale for the development of individual SGLT2 and SGLT1 inhibitors, as well as dual SGLT1/2 inhibition, including, but not limited to, aspects of genetics, genetically modified mouse models, mathematical modelling and general considerations of drug discovery in the field of metabolism.
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pmid30132033
doi10.1007/s00125-018-4654-7
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