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

Diabetes. 2011 Mar;60(3):890-8. doi: 10.2337/db10-1328.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Analysis of Variance
  • Animals
  • Apoptosis / genetics
  • Dietary Fats / metabolism
  • Glucose / metabolism*
  • Homeostasis / genetics*
  • Hyperglycemia / genetics
  • Hyperglycemia / metabolism
  • Hyperglycemia / physiopathology
  • 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*
  • Obesity / physiopathology
  • Sodium-Glucose Transporter 2 / genetics
  • Sodium-Glucose Transporter 2 / metabolism*

Substances

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