SGLT2 deletion improves glucose homeostasis and preserves pancreatic beta-cell function.
Details
Serval ID
serval:BIB_3D030338A6FB
Type
Article: article from journal or magazin.
Collection
Publications
Institution
Title
SGLT2 deletion improves glucose homeostasis and preserves pancreatic beta-cell function.
Journal
Diabetes
ISSN
1939-327X (Electronic)
ISSN-L
0012-1797
Publication state
Published
Issued date
2011
Volume
60
Number
3
Pages
890-898
Language
english
Notes
Publication types: Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov'tPublication Status: ppublish
Abstract
OBJECTIVE: Inhibition of the Na(+)-glucose cotransporter type 2 (SGLT2) is currently being pursued as an insulin-independent treatment for diabetes; however, the behavioral and metabolic consequences of SGLT2 deletion are unknown. Here, we used a SGLT2 knockout mouse to investigate the effect of increased renal glucose excretion on glucose homeostasis, insulin sensitivity, and pancreatic β-cell function.
RESEARCH DESIGN AND METHODS: SGLT2 knockout mice were fed regular chow or a high-fat diet (HFD) for 4 weeks, or backcrossed onto the db/db background. The analysis used metabolic cages, glucose tolerance tests, euglycemic and hyperglycemic clamps, as well as isolated islet and perifusion studies.
RESULTS: SGLT2 deletion resulted in a threefold increase in urine output and a 500-fold increase in glucosuria, as well as compensatory increases in feeding, drinking, and activity. SGLT2 knockout mice were protected from HFD-induced hyperglycemia and glucose intolerance and had reduced plasma insulin concentrations compared with controls. On the db/db background, SGLT2 deletion prevented fasting hyperglycemia, and plasma insulin levels were also dramatically improved. Strikingly, prevention of hyperglycemia by SGLT2 knockout in db/db mice preserved pancreatic β-cell function in vivo, which was associated with a 60% increase in β-cell mass and reduced incidence of β-cell death.
CONCLUSIONS: Prevention of renal glucose reabsorption by SGLT2 deletion reduced HFD- and obesity-associated hyperglycemia, improved glucose intolerance, and increased glucose-stimulated insulin secretion in vivo. Taken together, these data support SGLT2 inhibition as a viable insulin-independent treatment of type 2 diabetes.
RESEARCH DESIGN AND METHODS: SGLT2 knockout mice were fed regular chow or a high-fat diet (HFD) for 4 weeks, or backcrossed onto the db/db background. The analysis used metabolic cages, glucose tolerance tests, euglycemic and hyperglycemic clamps, as well as isolated islet and perifusion studies.
RESULTS: SGLT2 deletion resulted in a threefold increase in urine output and a 500-fold increase in glucosuria, as well as compensatory increases in feeding, drinking, and activity. SGLT2 knockout mice were protected from HFD-induced hyperglycemia and glucose intolerance and had reduced plasma insulin concentrations compared with controls. On the db/db background, SGLT2 deletion prevented fasting hyperglycemia, and plasma insulin levels were also dramatically improved. Strikingly, prevention of hyperglycemia by SGLT2 knockout in db/db mice preserved pancreatic β-cell function in vivo, which was associated with a 60% increase in β-cell mass and reduced incidence of β-cell death.
CONCLUSIONS: Prevention of renal glucose reabsorption by SGLT2 deletion reduced HFD- and obesity-associated hyperglycemia, improved glucose intolerance, and increased glucose-stimulated insulin secretion in vivo. Taken together, these data support SGLT2 inhibition as a viable insulin-independent treatment of type 2 diabetes.
Keywords
Analysis of Variance, Animals, Apoptosis/genetics, Dietary Fats/metabolism, Glucose/metabolism, Homeostasis/genetics, Hyperglycemia/genetics, Hyperglycemia/metabolism, Insulin/blood, Insulin Resistance, Insulin-Secreting Cells/metabolism, Islets of Langerhans/metabolism, Islets of Langerhans/physiopathology, Kidney/metabolism, Mice, Mice, Knockout, Obesity/genetics, Obesity/metabolism, Sodium-Glucose Transporter 2/genetics, Sodium-Glucose Transporter 2/metabolism
Pubmed
Web of science
Open Access
Yes
Create date
10/09/2015 13:47
Last modification date
20/08/2019 14:33