title: 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.
  
  
  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.affiliation: Howard Hughes Medical Institute, Yale University School of Medicine, New Haven, Connecticut, USA.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Jurczak
authors.forename: Hui-Young
authors.initials: HY
authors.lastname: Lee
authors.forename: Andreas L
authors.initials: AL
authors.lastname: Birkenfeld
authors.forename: Francois R
authors.initials: FR
authors.lastname: Jornayvaz
authors.forename: David W
authors.initials: DW
authors.lastname: Frederick
authors.forename: Rebecca L
authors.initials: RL
authors.lastname: Pongratz
authors.forename: Xiaoxian
authors.initials: X
authors.lastname: Zhao
authors.forename: Gilbert W
authors.initials: GW
authors.lastname: Moeckel
authors.forename: Varman T
authors.initials: VT
authors.lastname: Samuel
authors.forename: Jean M
authors.initials: JM
authors.lastname: Whaley
authors.forename: Gerald I
authors.initials: GI
authors.lastname: Shulman
authors.forename: Richard G
authors.initials: RG
authors.lastname: Kibbey
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D017209:Apoptosis / Q000235:genetics; D004041:Dietary Fats / Q000378:metabolism; D005947:Glucose / Q000378:metabolism*; D006706:Homeostasis / Q000235:genetics*; D006943:Hyperglycemia / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology; D007328:Insulin / Q000097:blood; D007333:Insulin Resistance; D050417:Insulin-Secreting Cells / Q000378:metabolism*; D007515:Islets of Langerhans / Q000378:metabolism / Q000503:physiopathology; D007668:Kidney / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D009765:Obesity / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D051297:Sodium-Glucose Transporter 2 / Q000235:genetics / Q000378:metabolism*
chemical_list: D004041:Dietary Fats; D007328:Insulin; C490299:Slc5a2 protein, mouse; D051297:Sodium-Glucose Transporter 2; D005947:Glucose