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David Polidori - One of the best experts on this subject based on the ideXlab platform.
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Glycaemic efficacy of canagliflozin is largely independent of baseline β-cell function or insulin sensitivity.
Diabetic Medicine, 2016Co-Authors: David R. Matthews, B. Zinman, Cindy Tong, Gary Meininger, David PolidoriAbstract:Canagliflozin is a sodium-glucose co-transporter 2 inhibitor approved for the treatment of adults with Type 2 diabetes. In phase III studies, canagliflozin reduced HbA1c, body weight and blood pressure, and was generally well tolerated [1–6]. Canagliflozin lowers plasma glucose by lowering the Renal Threshold for glucose and increasing urinary glucose excretion [7,8]. This article is protected by copyright. All rights reserved.
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Determination of the Renal Threshold for Glucose Excretion in Familial Renal Glucosuria
Nephron, 2015Co-Authors: Inês Aires, David Polidori, Marc Fila, Ana Rita Santos, Ana Brito Costa, Joaquim CaladoAbstract:Background/Aims: Familial Renal Glucosuria (FRG) is characterized by the presence of persistent isolated glucosuria in the absence of hyperglycemia. Mutations in SLC5A2, the gene coding for the sodium-glucose co-transporter 2 (SGLT2), are responsible for FRG. Phenotype/genotype correlations in FRG have mostly relied on the quantification of Urinary Glucose Excretion (UGE), which is dependent on both the filtered glucose load and the Renal glucose reabsorptive capacity. In the current work, the Renal Threshold for glucose excretion (RTG) was determined in an FRG cohort, with the purpose of characterizing the impact of SGLT2 mutations on Renal glucose transport. Methods: From January to December of 2013, eight FRG individuals with identified SLC5A2 mutations were enrolled. Patients were given a Mixed-Meal Tolerance Test during which blood glucose and UGE were measured over a 4 h period and the data was used to calculate RTG, according to a recently validated protocol. Results: In patients with homozygous mutations, RTG values were very low, with a mean (SD) of 0.95 (1.17) mmol/l, compared to commonly reported values of approximately 10-11.1 mmol/l in healthy subjects. In subjects with heterozygous mutations, mean (SD) RTG values were 4.91 (1.23) mmol/l, which are approximately one-half of the values in subjects without mutations. Conclusions: In FRG, mutations in SLC5A2 lead to reductions in RTG and increases in UGE. Because determination of RTG is not influenced by the filtered glucose load, the calculated RTG values provide a more refined measure of the impact of mutations on Renal glucose transport than can be obtained from UGE alone.
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Impaired decline in Renal Threshold for glucose during pregnancy - a possible novel mechanism for gestational diabetes mellitus.
Diabetes Metabolism Research and Reviews, 2014Co-Authors: Pinchas Klein, David Polidori, Orit Twito, Anat JaffeAbstract:Background The Renal Threshold for glucose (RTG) is determined by the nephron's reabsorptive capacity. Glucose is reabsorbed through sodium-coupled glucose cotransporters in the proximal tubules. During pregnancy, Renal glucose reabsorptive capacity decreases, possibly, due to reduced glucose transporter expression. Our hypothesis is that inadequate decrease in RTG during pregnancy will make women more prone to develop gestational diabetes mellitus (GDM). Methods Pregnant women (n = 40) who were referred to our center for oral glucose tolerance test (OGTT) were included in the analysis. Plasma glucose levels and urinary glucose excretion were measured for 4 h after 100 g oral glucose load. These data were used to calculate RTG. The subjects were divided into two cohorts, GDM and non-GDM, according to the OGTT results. Mean RTG was compared between the two groups. Results Fifteen (37.5%) of the women were diagnosed with GDM. Seventeen participants had only trace amounts of urinary glucose excretion, and no value of RTG could be determined; RTG was determined in the other 23 subjects. Among these 23 women, 13 were diagnosed as GDM, and 10 had normal OGTT. RTG was lower in the non-GDM women (146 ± 14 mg/dL) than in the GDM women (182 ± 18 mg/dL), p
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impaired decline in Renal Threshold for glucose during pregnancy a possible novel mechanism for gestational diabetes mellitus
Diabetes-metabolism Research and Reviews, 2014Co-Authors: Pinchas Klein, David Polidori, Orit Twito, Anat JaffeAbstract:Background The Renal Threshold for glucose (RTG) is determined by the nephron's reabsorptive capacity. Glucose is reabsorbed through sodium-coupled glucose cotransporters in the proximal tubules. During pregnancy, Renal glucose reabsorptive capacity decreases, possibly, due to reduced glucose transporter expression. Our hypothesis is that inadequate decrease in RTG during pregnancy will make women more prone to develop gestational diabetes mellitus (GDM). Methods Pregnant women (n = 40) who were referred to our center for oral glucose tolerance test (OGTT) were included in the analysis. Plasma glucose levels and urinary glucose excretion were measured for 4 h after 100 g oral glucose load. These data were used to calculate RTG. The subjects were divided into two cohorts, GDM and non-GDM, according to the OGTT results. Mean RTG was compared between the two groups. Results Fifteen (37.5%) of the women were diagnosed with GDM. Seventeen participants had only trace amounts of urinary glucose excretion, and no value of RTG could be determined; RTG was determined in the other 23 subjects. Among these 23 women, 13 were diagnosed as GDM, and 10 had normal OGTT. RTG was lower in the non-GDM women (146 ± 14 mg/dL) than in the GDM women (182 ± 18 mg/dL), p < 0.001. Conclusions Gestational diabetes mellitus is associated with higher RTG during pregnancy compared with non-GDM. These results support our hypothesis that inadequate decrease of the RTG may have a pathophysiological role in the development of GDM. Copyright © 2013 John Wiley & Sons, Ltd.
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validation of a novel method for determining the Renal Threshold for glucose excretion in untreated and canagliflozin treated subjects with type 2 diabetes mellitus
The Journal of Clinical Endocrinology and Metabolism, 2013Co-Authors: David Polidori, Atalanta Ghosh, Leona Plummorschel, Tim Heise, Paul RothenbergAbstract:Context: The stepwise hyperglycemic clamp procedure (SHCP) is the gold standard for measuring the Renal Threshold for glucose excretion (RTG), but its use is limited to small studies in specialized laboratories. Objective: The objective of the study was to validate a new method for determining RTG using data obtained during a mixed-meal tolerance test (MMTT) in untreated and canagliflozin-treated subjects with type 2 diabetes mellitus (T2DM). Design: This was an open-label study with 2 sequential parts. Setting: The study was performed at a single center in Germany. Patients: Twenty-eight subjects with T2DM were studied. Interventions: No treatment intervention was given in part 1. In part 2, subjects were treated with canagliflozin 100 mg/d for 8 days. In each part, subjects underwent an MMTT and a 5-step SHCP on consecutive days. Main Outcome Measures: For both methods, RTG was estimated using measured blood glucose (BG) and urinary glucose excretion (UGE); estimated glomerular filtration rates were als...
Pamela Rothenberg - One of the best experts on this subject based on the ideXlab platform.
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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 Obesity and Metabolism, 2011Co-Authors: S Sha, K Shalayda, David Polidori, Damayanthi Devineni, Keith T. Demarest, S. Chien, Deborah J Wexler, A. Ghosh, Pamela RothenbergAbstract:Abstract Canagliflozin, a potent, selective sodium glucose co-transporter 2 inhibitor in development for treatment of type 2 diabetes, lowers plasma glucose (PG) by lowering the Renal Threshold for glucose (RT(G) ) and increasing urinary glucose excretion (UGE). An ascending single oral-dose phase 1 study investigated safety, tolerability and pharmacodynamics of canagliflozin in healthy men (N = 63) randomized to receive canagliflozin (n = 48) or placebo (n = 15). Canagliflozin (10, 30, 100, 200, 400, 600 or 800 mg q.d. or 400 mg b.i.d.) was administered to eight cohorts (six subjects/cohort: canagliflozin; two subjects/cohort: placebo). Dose dependently, canagliflozin decreased calculated 24-h mean RT(G) with maximal reduction to approximately 60 mg/dl, and increased mean 24-h UGE. At doses >200 mg administered before breakfast, canagliflozin reduced postprandial PG and serum insulin excursions at that meal. Canagliflozin was generally well tolerated; most adverse events were mild and no hypoglycaemia was reported. These results support further study of canagliflozin.
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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 Obesity and Metabolism, 2011Co-Authors: S Sha, K Shalayda, David Polidori, Damayanthi Devineni, Keith T. Demarest, S. Chien, Deborah J Wexler, A. Ghosh, Pamela RothenbergAbstract:Abstract Canagliflozin, a potent, selective sodium glucose co-transporter 2 inhibitor in development for treatment of type 2 diabetes, lowers plasma glucose (PG) by lowering the Renal Threshold for glucose (RT(G) ) and increasing urinary glucose excretion (UGE). An ascending single oral-dose phase 1 study investigated safety, tolerability and pharmacodynamics of canagliflozin in healthy men (N = 63) randomized to receive canagliflozin (n = 48) or placebo (n = 15). Canagliflozin (10, 30, 100, 200, 400, 600 or 800 mg q.d. or 400 mg b.i.d.) was administered to eight cohorts (six subjects/cohort: canagliflozin; two subjects/cohort: placebo). Dose dependently, canagliflozin decreased calculated 24-h mean RT(G) with maximal reduction to approximately 60 mg/dl, and increased mean 24-h UGE. At doses >200 mg administered before breakfast, canagliflozin reduced postprandial PG and serum insulin excursions at that meal. Canagliflozin was generally well tolerated; most adverse events were mild and no hypoglycaemia was reported. These results support further study of canagliflozin.
Yawara Niijima - One of the best experts on this subject based on the ideXlab platform.
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Lower Renal Threshold for Glucose Reabsorption in Type 1 Diabetes Mellitus (T1DM) May Explain the Smaller Contribution of SGLT2 Inhibitors to the Improvement of Plasma Glucose Control Compared with T2DM.
Diabetes Therapy, 2019Co-Authors: Aya Osaki, Shuichi Okada, Tsugumichi Saito, Eijiro Yamada, Yawara Niijima, Yoko Shimoda, Junichi Okada, Yasuyo Nakajima, Atsushi Ozawa, Masanobu YamadaAbstract:Introduction Previously, we reported that the Renal Threshold for glucose reabsorption can be measured as the lowest plasma glucose level that correlates with the first detectable appearance of urine glucose. These data revealed significant variations among patients with type 2 diabetes mellitus (T2DM), and there was a significant negative correlation between the Renal Threshold for glucose reabsorption and HbA1c levels following treatment with the sodium-glucose co-transporter 2 (SGLT2) inhibitor ipragliflozin. Recently approved SGLT inhibitors may not show the same efficacy in patients with T1DM as in those with T2DM unless the Renal Threshold for glucose reabsorption shows similar levels between the two groups. SGLT2 inhibitors improve plasma glucose control in patients with T2DM by reducing glucose reabsorption via the epithelial cells of the proximal tubule. Methods The Renal Threshold for glucose reabsorption was defined as the minimum blood glucose concentration that results in the presence of measurable glycosuria in at least 12 measurements. Results The Renal Threshold for glucose reabsorption in patients with T2DM [n = 64; 201.8 ± 33.6 (range 121-268) mg/dL] was significantly higher than that in patients with T1DM [n = 33; 171.0 ± 33.0 (range 76-259) mg/dL; p = 0.00022]. Conclusion The Renal Threshold for glucose reabsorption in patients with T1DM was near the normal range and significantly lower than that in patients with T2DM. The efficacy of the SGLT2 inhibitor was better in patients with a higher Renal Threshold for glucose reabsorption. Thus, these results indicate that it is advisable to estimate the Renal Threshold for glucose reabsorption prior to initiating SGLT2 inhibitor therapy in patients with T1DM.
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lower Renal Threshold for glucose reabsorption in type 1 diabetes mellitus t1dm may explain the smaller contribution of sglt2 inhibitors to the improvement of plasma glucose control compared with t2dm
Diabetes Therapy, 2019Co-Authors: Aya Osaki, Tsugumichi Saito, Eijiro Yamada, Yawara Niijima, Yoko Shimoda, Junichi Okada, Yasuyo Nakajima, Atsushi OzawaAbstract:Previously, we reported that the Renal Threshold for glucose reabsorption can be measured as the lowest plasma glucose level that correlates with the first detectable appearance of urine glucose. These data revealed significant variations among patients with type 2 diabetes mellitus (T2DM), and there was a significant negative correlation between the Renal Threshold for glucose reabsorption and HbA1c levels following treatment with the sodium-glucose co-transporter 2 (SGLT2) inhibitor ipragliflozin. Recently approved SGLT inhibitors may not show the same efficacy in patients with T1DM as in those with T2DM unless the Renal Threshold for glucose reabsorption shows similar levels between the two groups. SGLT2 inhibitors improve plasma glucose control in patients with T2DM by reducing glucose reabsorption via the epithelial cells of the proximal tubule. The Renal Threshold for glucose reabsorption was defined as the minimum blood glucose concentration that results in the presence of measurable glycosuria in at least 12 measurements. The Renal Threshold for glucose reabsorption in patients with T2DM [n = 64; 201.8 ± 33.6 (range 121–268) mg/dL] was significantly higher than that in patients with T1DM [n = 33; 171.0 ± 33.0 (range 76–259) mg/dL; p = 0.00022]. The Renal Threshold for glucose reabsorption in patients with T1DM was near the normal range and significantly lower than that in patients with T2DM. The efficacy of the SGLT2 inhibitor was better in patients with a higher Renal Threshold for glucose reabsorption. Thus, these results indicate that it is advisable to estimate the Renal Threshold for glucose reabsorption prior to initiating SGLT2 inhibitor therapy in patients with T1DM.
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Renal Threshold for glucose reabsorption predicts diabetes improvement by sodium-glucose cotransporter 2 inhibitor therapy.
Journal of Diabetes Investigation, 2016Co-Authors: Aya Osaki, Shuichi Okada, Tsugumichi Saito, Eijiro Yamada, Kumeo Ono, Yawara Niijima, Hiroto Hoshi, Masanobu YamadaAbstract:In the present study we examined the efficacy of sodium-glucose cotransporter 2 inhibitors on improvement of glycated hemoglobin (HbA1c) in comparison with the Renal Threshold for glucose reabsorption in patients with type 2 diabetes mellitus. Patients visited the hospital once a month for a regular follow-up examination with the determination of blood glucose and HbA1c levels, and urinary glucose concentration from spot urine samples. Patient samples were compared before and after ipragliflozin administration. We defined the Renal Threshold for glucose reabsorption as the lowest blood glucose level that correlated with the first detectable appearance of urine glucose. These data showed a significant negative correlation between improvement of HbA1c level and Renal Threshold for glucose reabsorption in patients treated with the sodium-glucose cotransporter 2 inhibitor. These findings show that patients who have a higher Renal Threshold for glucose reabsorption can be expected to more effectively respond to sodium-glucose cotransporter 2 inhibitor therapy in terms of lowering HbA1c levels.
S Sha - One of the best experts on this subject based on the ideXlab platform.
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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 Obesity and Metabolism, 2011Co-Authors: S Sha, K Shalayda, David Polidori, Damayanthi Devineni, Keith T. Demarest, S. Chien, Deborah J Wexler, A. Ghosh, Pamela RothenbergAbstract:Abstract Canagliflozin, a potent, selective sodium glucose co-transporter 2 inhibitor in development for treatment of type 2 diabetes, lowers plasma glucose (PG) by lowering the Renal Threshold for glucose (RT(G) ) and increasing urinary glucose excretion (UGE). An ascending single oral-dose phase 1 study investigated safety, tolerability and pharmacodynamics of canagliflozin in healthy men (N = 63) randomized to receive canagliflozin (n = 48) or placebo (n = 15). Canagliflozin (10, 30, 100, 200, 400, 600 or 800 mg q.d. or 400 mg b.i.d.) was administered to eight cohorts (six subjects/cohort: canagliflozin; two subjects/cohort: placebo). Dose dependently, canagliflozin decreased calculated 24-h mean RT(G) with maximal reduction to approximately 60 mg/dl, and increased mean 24-h UGE. At doses >200 mg administered before breakfast, canagliflozin reduced postprandial PG and serum insulin excursions at that meal. Canagliflozin was generally well tolerated; most adverse events were mild and no hypoglycaemia was reported. These results support further study of canagliflozin.
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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 Obesity and Metabolism, 2011Co-Authors: S Sha, K Shalayda, David Polidori, Damayanthi Devineni, Keith T. Demarest, S. Chien, Deborah J Wexler, A. Ghosh, Pamela RothenbergAbstract:Abstract Canagliflozin, a potent, selective sodium glucose co-transporter 2 inhibitor in development for treatment of type 2 diabetes, lowers plasma glucose (PG) by lowering the Renal Threshold for glucose (RT(G) ) and increasing urinary glucose excretion (UGE). An ascending single oral-dose phase 1 study investigated safety, tolerability and pharmacodynamics of canagliflozin in healthy men (N = 63) randomized to receive canagliflozin (n = 48) or placebo (n = 15). Canagliflozin (10, 30, 100, 200, 400, 600 or 800 mg q.d. or 400 mg b.i.d.) was administered to eight cohorts (six subjects/cohort: canagliflozin; two subjects/cohort: placebo). Dose dependently, canagliflozin decreased calculated 24-h mean RT(G) with maximal reduction to approximately 60 mg/dl, and increased mean 24-h UGE. At doses >200 mg administered before breakfast, canagliflozin reduced postprandial PG and serum insulin excursions at that meal. Canagliflozin was generally well tolerated; most adverse events were mild and no hypoglycaemia was reported. These results support further study of canagliflozin.
Deborah J Wexler - One of the best experts on this subject based on the ideXlab platform.
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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 Obesity and Metabolism, 2011Co-Authors: S Sha, K Shalayda, David Polidori, Damayanthi Devineni, Keith T. Demarest, S. Chien, Deborah J Wexler, A. Ghosh, Pamela RothenbergAbstract:Abstract Canagliflozin, a potent, selective sodium glucose co-transporter 2 inhibitor in development for treatment of type 2 diabetes, lowers plasma glucose (PG) by lowering the Renal Threshold for glucose (RT(G) ) and increasing urinary glucose excretion (UGE). An ascending single oral-dose phase 1 study investigated safety, tolerability and pharmacodynamics of canagliflozin in healthy men (N = 63) randomized to receive canagliflozin (n = 48) or placebo (n = 15). Canagliflozin (10, 30, 100, 200, 400, 600 or 800 mg q.d. or 400 mg b.i.d.) was administered to eight cohorts (six subjects/cohort: canagliflozin; two subjects/cohort: placebo). Dose dependently, canagliflozin decreased calculated 24-h mean RT(G) with maximal reduction to approximately 60 mg/dl, and increased mean 24-h UGE. At doses >200 mg administered before breakfast, canagliflozin reduced postprandial PG and serum insulin excursions at that meal. Canagliflozin was generally well tolerated; most adverse events were mild and no hypoglycaemia was reported. These results support further study of canagliflozin.
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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 Obesity and Metabolism, 2011Co-Authors: S Sha, K Shalayda, David Polidori, Damayanthi Devineni, Keith T. Demarest, S. Chien, Deborah J Wexler, A. Ghosh, Pamela RothenbergAbstract:Abstract Canagliflozin, a potent, selective sodium glucose co-transporter 2 inhibitor in development for treatment of type 2 diabetes, lowers plasma glucose (PG) by lowering the Renal Threshold for glucose (RT(G) ) and increasing urinary glucose excretion (UGE). An ascending single oral-dose phase 1 study investigated safety, tolerability and pharmacodynamics of canagliflozin in healthy men (N = 63) randomized to receive canagliflozin (n = 48) or placebo (n = 15). Canagliflozin (10, 30, 100, 200, 400, 600 or 800 mg q.d. or 400 mg b.i.d.) was administered to eight cohorts (six subjects/cohort: canagliflozin; two subjects/cohort: placebo). Dose dependently, canagliflozin decreased calculated 24-h mean RT(G) with maximal reduction to approximately 60 mg/dl, and increased mean 24-h UGE. At doses >200 mg administered before breakfast, canagliflozin reduced postprandial PG and serum insulin excursions at that meal. Canagliflozin was generally well tolerated; most adverse events were mild and no hypoglycaemia was reported. These results support further study of canagliflozin.