Renal Glucose Reabsorption in Response to Dapagliflozin
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.
The current study was undertaken to examine the mechanism (decreased maximum renal glucose reabsorptive capacity [TmG], increased splay, and reduced threshold) through which sodium-glucose transporter 2 (SGLT2) inhibition induces glucosuria in diabetic and nondiabetic subjects. In humans, the kidney filters ~162 g of glucose per day (glomerular filtration rate [GFR] = 180 L/day × fasting plasma glucose [FPG] = ~5 mmol/L [90 mg/dL]), and virtually all the filtered glucose is reabsorbed. The high-capacity, low-affinity SGLT2 in the proximal tubule reabsorbs ~80–90% of filtered glucose.TmG varies among individuals and averages ~375 mg/min. Because the filtered glucose load does not exceed TmG in nondiabetic individuals, all filtered glucose is reabsorbed and returned to the circulation. If the filtered glucose load exceeds the TmG, all glucose in excess of the TmG is excreted. The plasma glucose concentration at which the filtered glucose load reaches 375 mg/min is ~10 mmol/L (180 mg/dL). Above the TmG, the glucose excretion rate increases linearly and parallels the increase in filtered glucose load. Glucose reabsorption and excretion curves display a nonlinear transition as TmG is approached. This rounding of the curves is termed splay (Fig. 1). The plasma glucose concentration at which glucose first appears in the urine is termed threshold and corresponds to the beginning of the splay.
(Enlarge Image)
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; â—‹, observed rate of reabsorption; thick line, predicted rate of reabsorption; dashed line, geometric mean of TmG.
In patients with poorly controlled type 1 or 2 diabetes, TmG is increased. Similar observations have been made in diabetic animal models. At the molecular level, increased TmG may be explained by increased SGLT2 mRNA and protein in the proximal tubule.
SGLT2 inhibitors have been developed for the treatment of type 2 diabetes and have proven to be efficacious in reducing glycated hemoglobin (HbA1c). Because their mechanism of action is independent of severity of insulin resistance and β-cell failure, they can be used at any stage of type 2 diabetes. Clinical trials with SGLT2 inhibitors have demonstrated that treatment in healthy subjects results in continuously excreted glucose in the absence of hyperglycemia, suggesting that factors other than a reduction in TmG must account for the drug's glucosuric effect. Because no previous study to our knowledge has comprehensively characterized the changes in renal glucose handling through which SGLT2 inhibitors augment renal glucose excretion in humans, the current study was undertaken to examine the mechanisms through which dapagliflozin produces its glucosuric effect in individuals with type 2 diabetes and those with normal glucose tolerance.
Abstract and Introduction
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.
Introduction
The current study was undertaken to examine the mechanism (decreased maximum renal glucose reabsorptive capacity [TmG], increased splay, and reduced threshold) through which sodium-glucose transporter 2 (SGLT2) inhibition induces glucosuria in diabetic and nondiabetic subjects. In humans, the kidney filters ~162 g of glucose per day (glomerular filtration rate [GFR] = 180 L/day × fasting plasma glucose [FPG] = ~5 mmol/L [90 mg/dL]), and virtually all the filtered glucose is reabsorbed. The high-capacity, low-affinity SGLT2 in the proximal tubule reabsorbs ~80–90% of filtered glucose.TmG varies among individuals and averages ~375 mg/min. Because the filtered glucose load does not exceed TmG in nondiabetic individuals, all filtered glucose is reabsorbed and returned to the circulation. If the filtered glucose load exceeds the TmG, all glucose in excess of the TmG is excreted. The plasma glucose concentration at which the filtered glucose load reaches 375 mg/min is ~10 mmol/L (180 mg/dL). Above the TmG, the glucose excretion rate increases linearly and parallels the increase in filtered glucose load. Glucose reabsorption and excretion curves display a nonlinear transition as TmG is approached. This rounding of the curves is termed splay (Fig. 1). The plasma glucose concentration at which glucose first appears in the urine is termed threshold and corresponds to the beginning of the splay.
(Enlarge Image)
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; â—‹, observed rate of reabsorption; thick line, predicted rate of reabsorption; dashed line, geometric mean of TmG.
In patients with poorly controlled type 1 or 2 diabetes, TmG is increased. Similar observations have been made in diabetic animal models. At the molecular level, increased TmG may be explained by increased SGLT2 mRNA and protein in the proximal tubule.
SGLT2 inhibitors have been developed for the treatment of type 2 diabetes and have proven to be efficacious in reducing glycated hemoglobin (HbA1c). Because their mechanism of action is independent of severity of insulin resistance and β-cell failure, they can be used at any stage of type 2 diabetes. Clinical trials with SGLT2 inhibitors have demonstrated that treatment in healthy subjects results in continuously excreted glucose in the absence of hyperglycemia, suggesting that factors other than a reduction in TmG must account for the drug's glucosuric effect. Because no previous study to our knowledge has comprehensively characterized the changes in renal glucose handling through which SGLT2 inhibitors augment renal glucose excretion in humans, the current study was undertaken to examine the mechanisms through which dapagliflozin produces its glucosuric effect in individuals with type 2 diabetes and those with normal glucose tolerance.
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