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

• Published in: Diabetes care Vol. 36; no. 10; pp. 3169 - 3176
• Main Authors: DeFronzo, Ralph A., Hompesch, Marcus, Kasichayanula, Sreeneeranj, Liu, Xiaoni, Hong, Ying, Pfister, Marc, Morrow, Linda A., Leslie, Bruce R., Boulton, David W., Ching, Agatha, LaCreta, Frank P., Griffen, Steven C.
• Format: Journal Article
• Language: English
• Published: Alexandria, VA American Diabetes Association 01.10.2013
• Subjects: Adult; Benzhydryl Compounds; Biological and medical sciences; Chemical properties; Dextrose; Diabetes; Diabetes Mellitus, Type 2 - drug therapy; Diabetes Mellitus, Type 2 - metabolism; Diabetes. Impaired glucose tolerance; Disease control; Endocrine pancreas. Apud cells (diseases); Endocrinopathies; Etiopathogenesis. Screening. Investigations. Target tissue resistance; Female; Glucose; Glucose - metabolism; Glucosides - therapeutic use; Humans; Hyperglycemia; Hypoglycemic Agents - therapeutic use; Kidney - metabolism; Male; Medical sciences; Metabolic diseases; Middle Aged; Original Research; Pharmaceutical industry; Pharmaceuticals; Pharmacology; Sodium-Glucose Transport Proteins - antagonists & inhibitors; Type 2 diabetes; United States; Endocrinopathy; Type 2 diabetes; Human; Healthy subject; Nutrition; Dapagliflozin; Metabolic diseases; Reabsorption; Glucose; Kidney; Characterization; Hypoglycemic agent; Urinary system; Endocrinology
• ISSN: 0149-5992; 1935-5548; 1935-5548
• DOI: 10.2337/dc13-0387

To 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 [TmG], increased splay, and reduced threshold), using the pancreatic/stepped hyperglycemic clamp (SHC) technique. Subjects 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. At baseline, type 2 diabetic subjects had elevated TmG, splay, and threshold compared with controls. Dapagliflozin treatment reduced the TmG 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. The SGLT2 inhibitor dapagliflozin improves glycemic control in diabetic patients by reducing the TmG and threshold at which glucose is excreted in the urine.