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

OBJECTIVE 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. RESEARCH DESIGN AND METHODS 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. RESULTS 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. CONCLUSIONS The SGLT2 inhibitor dapagliflozin improves glycemic control in diabetic patients by reducing the TmG and threshold at which glucose is excreted in the urine.

[1]  D. Earle,et al.  Effect of diabetes and insulin of the maximum capacity of the renal tubules to reabsorb glucose. , 1951, The Journal of clinical investigation.

[2]  C. Mogensen.  Urinary albumin excretion in early and long-term juvenile diabetes. , 1971, Scandinavian journal of clinical and laboratory investigation.

[3]  R. DeFronzo,et al.  Glucose clamp technique: a method for quantifying insulin secretion and resistance. , 1979, The American journal of physiology.

[4]  Heinz Valtin,et al.  Renal Function: Mechanisms Preserving Fluid and Solute Balance in Health , 1983 .

[5]  L Heinemann,et al.  Glucose Clamps with the Biostator: A Critical Reappraisal , 1994, Hormone and metabolic research = Hormon- und Stoffwechselforschung = Hormones et metabolisme.

[6]  V. M. Shapiro,et al.  Renal glucose reabsorption during hypertonic glucose infusion in female streptozotocin-induced diabetic rats. , 2001, Life sciences.

[7]  E. Debnam,et al.  Diabetes Increases Facilitative Glucose Uptake and GLUT2 Expression at the Rat Proximal Tubule Brush Border Membrane , 2003, The Journal of physiology.

[8]  Chari D Smith,et al.  Glucose transporters in human renal proximal tubular cells isolated from the urine of patients with non-insulin-dependent diabetes. , 2005, Diabetes.

[9]  Tom Greene,et al.  Assessing kidney function--measured and estimated glomerular filtration rate. , 2006, The New England journal of medicine.

[10]  Yoshikazu Fujimori,et al.  Sergliflozin, a Novel Selective Inhibitor of Low-Affinity Sodium Glucose Cotransporter (SGLT2), Validates the Critical Role of SGLT2 in Renal Glucose Reabsorption and Modulates Plasma Glucose Level , 2007, Journal of Pharmacology and Experimental Therapeutics.

[11]  G. Sterner,et al.  Determining ‘true’ glomerular filtration rate in healthy adults using infusion of inulin and comparing it with values obtained using other clearance techniques or prediction equations , 2008, Scandinavian journal of urology and nephrology.

[12]  M. Okamoto,et al.  Na(+) -glucose transporter-2 messenger ribonucleic acid expression in kidney of diabetic rats correlates with glycemic levels: involvement of hepatocyte nuclear factor-1alpha expression and activity. , 2008, Endocrinology.

[13]  Enrique Morales,et al.  Sodium-Glucose Cotransport Inhibition With Dapagliflozin in Type 2 Diabetes , 2008, Diabetes Care.

[14]  D. Boulton,et al.  Dapagliflozin, a Novel SGLT2 Inhibitor, Induces Dose‐Dependent Glucosuria in Healthy Subjects , 2009, Clinical pharmacology and therapeutics.

[15]  M. Pfister,et al.  Dapagliflozin, a Novel, Selective SGLT2 Inhibitor, Improved Glycemic Control Over 2 Weeks in Patients With Type 2 Diabetes Mellitus , 2009, Clinical pharmacology and therapeutics.

[16]  P. Norwood,et al.  A Study of Dapagliflozin in Patients With Type 2 Diabetes Receiving High Doses of Insulin Plus Insulin Sensitizers , 2009, Diabetes Care.

[17]  Ralph A. DeFronzo,et al.  From the Triumvirate to the Ominous Octet: A New Paradigm for the Treatment of Type 2 Diabetes Mellitus , 2009, Diabetes.

[18]  C. Bailey,et al.  Effect of dapagliflozin in patients with type 2 diabetes who have inadequate glycaemic control with metformin: a randomised, double-blind, placebo-controlled trial , 2010, The Lancet.

[19]  M. Pfister,et al.  Dapagliflozin treatment in patients with different stages of type 2 diabetes mellitus: effects on glycaemic control and body weight , 2010, Diabetes, obesity & metabolism.

[20]  E. Ferrannini,et al.  Dapagliflozin Monotherapy in Type 2 Diabetic Patients With Inadequate Glycemic Control by Diet and Exercise , 2010, Diabetes Care.

[21]  H. Koepsell,et al.  SGLT2 mediates glucose reabsorption in the early proximal tubule , 2010, Journal of the American Society of Nephrology : JASN.

[22]  D. Loo,et al.  Biology of human sodium glucose transporters. , 2011, Physiological reviews.

[23]  D. Wexler,et al.  Canagliflozin, a novel inhibitor of sodium glucose co‐transporter 2, dose dependently reduces calculated renal threshold for glucose excretion and increases urinary glucose excretion in healthy subjects , 2011, Diabetes, obesity & metabolism.

[24]  R. DeFronzo,et al.  Role of sodium-glucose cotransporter 2 (SGLT 2) inhibitors in the treatment of type 2 diabetes. , 2011, Endocrine reviews.

[25]  Ralph A. DeFronzo,et al.  Why Do SGLT2 Inhibitors Inhibit Only 30–50% of Renal Glucose Reabsorption in Humans? , 2012, Diabetes.

[26]  F. Mseeh,et al.  Improved glycemic control in mice lacking Sglt1 and Sglt2. , 2013, American journal of physiology. Endocrinology and metabolism.