Characterization of Renal Glucose Reabsorption in Response to Dapagliflozin in Healthy Subjects and Subjects With Type 2 Diabetes

被引:257
作者
DeFronzo, Ralph A. [1 ]
Hompesch, Marcus [2 ]
Kasichayanula, Sreeneeranj [3 ]
Liu, Xiaoni [4 ]
Hong, Ying [3 ]
Pfister, Marc [3 ]
Morrow, Linda A. [2 ]
Leslie, Bruce R. [5 ]
Boulton, David W. [3 ]
Ching, Agatha [6 ]
LaCreta, Frank P. [3 ]
Griffen, Steven C. [3 ]
机构
[1] Univ Texas Hlth Sci Ctr San Antonio, Dept Med, Diabet Div, San Antonio, TX 78229 USA
[2] Profil Inst Clin Res, Chula Vista, CA USA
[3] Bristol Myers Squibb Co, Discovery Med & Clin Pharmacol, Princeton, NJ USA
[4] Bristol Myers Squibb Co, Global Biometr Sci, Princeton, NJ USA
[5] Bristol Myers Squibb Co, Global Clin Res, Princeton, NJ USA
[6] Bristol Myers Squibb Co, BioPharma Project Management, Princeton, NJ USA
关键词
INADEQUATE GLYCEMIC CONTROL; GLOMERULAR-FILTRATION-RATE; SGLT2; INHIBITOR; DOUBLE-BLIND; MELLITUS; TRANSPORTERS; EXPRESSION; INFUSION; KIDNEY; TRIAL;
D O I
10.2337/dc13-0387
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
OBJECTIVETo examine the effect of dapagliflozin, a sodium-glucose cotransporter 2 (SGLT2) inhibitor, on the major components of renal glucose reabsorption (decreased maximum renal glucose reabsorptive capacity [T-mG], increased splay, and reduced threshold), using the pancreatic/stepped hyperglycemic clamp (SHC) technique.RESEARCH DESIGN AND METHODSSubjects with type 2 diabetes (n = 12) and matched healthy subjects (n = 12) underwent pancreatic/SHC (plasma glucose range 5.5-30.5 mmol/L) at baseline and after 7 days of dapagliflozin treatment. A pharmacodynamic model was developed to describe the major components of renal glucose reabsorption for both groups and then used to estimate these parameters from individual glucose titration curves.RESULTSAt baseline, type 2 diabetic subjects had elevated T-mG, splay, and threshold compared with controls. Dapagliflozin treatment reduced the T-mG and splay in both groups. However, the most significant effect of dapagliflozin was a reduction of the renal threshold for glucose excretion in type 2 diabetic and control subjects.CONCLUSIONSThe SGLT2 inhibitor dapagliflozin improves glycemic control in diabetic patients by reducing the T-mG and threshold at which glucose is excreted in the urine.
引用
收藏
页码:3169 / 3176
页数:8
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