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Randomized Controlled Trial
. 2013 Oct;36(10):3169-76.
doi: 10.2337/dc13-0387. Epub 2013 Jun 4.

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

Ralph A DeFronzo  1 , 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
Affiliations
Randomized Controlled Trial

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

Ralph A DeFronzo et al. Diabetes Care. 2013 Oct.

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.

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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.
See this image and copyright information in PMC

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