SGLT2 deletion improves glucose homeostasis and preserves pancreatic beta-cell function.

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.

• Authors: Michael J Jurczak, Hui-Young Lee, Andreas L Birkenfeld, Francois R Jornayvaz, David W Frederick, Rebecca L Pongratz, Xiaoxian Zhao, Gilbert W Moeckel, Varman T Samuel, Jean M Whaley, Gerald I Shulman, Richard G Kibbey
• Journal: Diabetes (Diabetes) Vol. 60 Issue 3 Pg. 890-8 (Mar 2011) ISSN: 1939-327X [Electronic] United States
• PMID: 21357472 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Dietary Fats
• Insulin
• Slc5a2 protein, mouse
• Sodium-Glucose Transporter 2
• Glucose

Topics

• Analysis of Variance
• Animals
• Apoptosis (genetics)
• Dietary Fats (metabolism)
• Glucose (metabolism)
• Homeostasis (genetics)
• Hyperglycemia (genetics, metabolism, physiopathology)
• Insulin (blood)
• Insulin Resistance
• Insulin-Secreting Cells (metabolism)
• Islets of Langerhans (metabolism, physiopathology)
• Kidney (metabolism)
• Mice
• Mice, Knockout
• Obesity (genetics, metabolism, physiopathology)
• Sodium-Glucose Transporter 2 (genetics, metabolism)