Characterization of renal glucose reabsorption in response to dapagliflozin in healthy subjects and subjects with type 2 diabetes

Ralph A DeFronzo, Marcus Hompesch, Sreeneeranj Kasichayanula, Xiaoni Liu, Ying Hong, Marc Pfister, Linda A Morrow, Bruce R Leslie, David W Boulton, Agatha Ching, Frank P LaCreta, Steven C Griffen, Ralph A DeFronzo, Marcus Hompesch, Sreeneeranj Kasichayanula, Xiaoni Liu, Ying Hong, Marc Pfister, Linda A Morrow, Bruce R Leslie, David W Boulton, Agatha Ching, Frank P LaCreta, Steven C Griffen

Abstract

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.

Figures

Figure 1
Figure 1
Relationship between the rate of urinary glucose reabsorption/renal glucose filtration and the plasma glucose concentration during SHC in type 2 diabetic and healthy subjects at baseline and after 7 days of dapagliflozin treatment. Thin line, rate of glucose filtration; ○, observed rate of reabsorption; thick line, predicted rate of reabsorption; dashed line, geometric mean of TmG.
Figure 2
Figure 2
TmG in type 2 diabetic and healthy subjects at baseline and after 7 days of dapagliflozin treatment. A: TmG for all subjects. B: TmG for all 12 subjects with type 2 diabetes and 11 healthy subjects minus 1 outlier, which is shown separately.
Figure 3
Figure 3
A: Relationship between urinary glucose secretion (mg per 40 min SHC) and target plasma glucose concentration in type 2 diabetic and healthy subjects before and after 7 days of dapagliflozin treatment. B: Percentage of the filtered glucose load appearing in the urine of type 2 diabetic and healthy subjects before and after 7 days of dapagliflozin treatment.

References

    1. Valtin H. Renal Function: Mechanism Preserving Fluid and Solute Balance in Health Boston, Little, Brown and Company, 1983
    1. Vallon V, Platt KA, Cunard R, et al. SGLT2 mediates glucose reabsorption in the early proximal tubule. J Am Soc Nephrol 2011;22:104–112
    1. Wright EM, Loo DD, Hirayama BA. Biology of human sodium glucose transporters. Physiol Rev 2011;91:733–794
    1. Abdul-Ghani MA, Norton L, Defronzo RA. Role of sodium-glucose cotransporter 2 (SGLT 2) inhibitors in the treatment of type 2 diabetes. Endocr Rev 2011;32:515–531
    1. Farber SJ, Berger EY, Earle DP. Effect of diabetes and insulin of the maximum capacity of the renal tubules to reabsorb glucose. J Clin Invest 1951;30:125–129
    1. Mogensen CE. Urinary albumin excretion in early and long-term juvenile diabetes. Scand J Clin Lab Invest 1971;28:183–193
    1. Katsuno K, Fujimori Y, Takemura Y, 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. J Pharmacol Exp Ther 2007;320:323–330
    1. Noonan WT, Shapiro VM, Banks RO. Renal glucose reabsorption during hypertonic glucose infusion in female streptozotocin-induced diabetic rats. Life Sci 2001;68:2967–2977
    1. Marks J, Carvou NJC, Debnam ES, Srai SK, Unwin RJ. Diabetes increases facilitative glucose uptake and GLUT2 expression at the rat proximal tubule brush border membrane. J Physiol 2003;553:137–145
    1. Freitas HS, Anhê GF, Melo KF, 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. Endocrinology 2008;149:717–724
    1. Rahmoune H, Thompson PW, Ward JM, Smith CD, Hong G, Brown J. Glucose transporters in human renal proximal tubular cells isolated from the urine of patients with non-insulin-dependent diabetes. Diabetes 2005;54:3427–3434
    1. Komoroski B, Vachharajani N, Feng Y, Li L, Kornhauser D, Pfister M. Dapagliflozin, a novel, selective SGLT2 inhibitor, improved glycemic control over 2 weeks in patients with type 2 diabetes mellitus. Clin Pharmacol Ther 2009;85:513–519
    1. List JF, Woo V, Morales E, Tang W, Fiedorek FT. Sodium-glucose cotransport inhibition with dapagliflozin in type 2 diabetes. Diabetes Care 2009;32:650–657
    1. Zhang L, Feng Y, List J, Kasichayanula S, Pfister M. Dapagliflozin treatment in patients with different stages of type 2 diabetes mellitus: effects on glycaemic control and body weight. Diabetes Obes Metab 2010;12:510–516
    1. Bailey CJ, Gross JL, Pieters A, Bastien A, List JF. Effect of dapagliflozin in patients with type 2 diabetes who have inadequate glycaemic control with metformin: a randomised, double-blind, placebo-controlled trial. Lancet 2010;375:2223–2233
    1. Ferrannini E, Ramos SJ, Salsali A, Tang W, List JF. Dapagliflozin monotherapy in type 2 diabetic patients with inadequate glycemic control by diet and exercise: a randomized, double-blind, placebo-controlled, phase 3 trial. Diabetes Care 2010;33:2217–2224
    1. Wilding JPH, Norwood P, T’joen C, Bastien A, List JF, Fiedorek FT. A study of dapagliflozin in patients with type 2 diabetes receiving high doses of insulin plus insulin sensitizers: applicability of a novel insulin-independent treatment. Diabetes Care 2009;32:1656–1662
    1. Komoroski B, Vachharajani N, Boulton D, et al. Dapagliflozin, a novel SGLT2 inhibitor, induces dose-dependent glucosuria in healthy subjects. Clin Pharmacol Ther 2009;85:520–526
    1. Sha S, Devineni D, Ghosh A, 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. Diabetes Obes Metab 2011;13:669–672
    1. Stevens LA, Coresh J, Greene T, Levey AS. Assessing kidney function—measured and estimated glomerular filtration rate. N Engl J Med 2006;354:2473–2483
    1. DeFronzo RA, Tobin JD, Andres R. Glucose clamp technique: a method for quantifying insulin secretion and resistance. Am J Physiol 1979;237:E214–E223
    1. Sterner G, Frennby B, Mansson S, Nyman U, Van Westen D, Almén T. 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. Scand J Urol Nephrol 2008;42:278–285
    1. Heinemann L, Ampudia-Blasco FJ. Glucose clamps with the Biostator: a critical reappraisal. Horm Metab Res 1994;26:579–583
    1. Defronzo RA. Banting Lecture. From the triumvirate to the ominous octet: a new paradigm for the treatment of type 2 diabetes mellitus. Diabetes 2009;58:773–795
    1. Liu JJ, Lee TW, DeFronzo RA. Why Do SGLT2 inhibitors inhibit only 30-50% of renal glucose reabsorption in humans? Diabetes 2012;61:2199–2204
    1. Powell DR, DaCosta CM, Gay J, et al. Improved glycemic control in mice lacking Sglt1 and Sglt2. Am J Physiol Endocrinol Metab 2013;304:E117–E130

Source: PubMed

Sponsors en medewerkers

Medische omstandigheden

Geneesmiddelinterventies

3
Abonneren