SGLT2 deletion improves glucose homeostasis and preserves pancreatic beta-cell function.
Diabetes
; 60(3): 890-8, 2011 Mar.
Article
in En
| MEDLINE
| ID: mdl-21357472
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 ß-cell function. RESEARCH DESIGN ANDMETHODS:
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 ß-cell function in vivo, which was associated with a 60% increase in ß-cell mass and reduced incidence of ß-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.
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Insulin-Secreting Cells
/
Sodium-Glucose Transporter 2
/
Glucose
/
Homeostasis
/
Obesity
Limits:
Animals
Language:
En
Journal:
Diabetes
Year:
2011
Document type:
Article
Affiliation country:
United States