Renal Threshold For Glucose Excretion Research Articles

Treatment with SGLT-2 inhibitors and urinary tract and genital infections risk

The kidneys are involved in the regulation of glucose homeostasis by reabsorbing glucose filtered into the glomerular filtrate. Reabsorption occurs in the proximal convoluted tubule and is carried out by two isoforms of the sodium-glucose cotransporters (SGLTs). SGLT-2 inhibitors suppress renal glucose reabsorption by lowering the renal threshold for glucose excretion by inhibiting SGLT-2 protein in the proximal tubule of the kidney. As a result, the excretion of glucose in the urine increases. SGLT-2 inhibitors have revolutionized the treatment of patients with type 2 diabetes mellitus with or without cardiovascular disease and patients with diabetic nephropathy. The mechanism of action, SGLT-2 inhibitors is associated with an increase in glycosuria, a risk factor for genital and urinary infections. Additional studies and monitoring of adverse side effects and complications of treatment with these medications are needed. The occurrence of mild to moderate genital and urinary tract infections can be treated according to good clinical practice guidelines for this type of disease, and the continuation of treatment should be determined individually for each patient.

Euglycemic DKA in Patients on SGLT2 Inhibitor and Potentially Ketotic State

Background: With mounting evidence demonstrating improved cardiovascular and renal outcomes with the use of sodium-glucose cotransporter-2 (SGLT2) inhibitors, this class of newest antidiabetic agents is rapidly gaining favor. SGLT2 inhibition lowers the renal threshold for glucose excretion, resulting in renal glycosuria, a shift in substrate utilization from carbohydrate to fat oxidation and hyperglucagonemia and thus poses the risk of developing euglycemic DKA as a rare but serious adverse effect. Clinical Cases: the first case is A 36-year-old female was diagnosed with type 2 DM with an HbA1c of 10% and was started on multi-agent antihyperglycemic therapy including metformin 500 mg BID, extended release exenatide 2 mg once a week and empagliflozin 25 mg once daily which were all initiated simultaneously. 2 days after starting regimen, she complained of nausea, vomiting and was unable to tolerate oral diet and fluids by day 4 which potentially predisposed to starvation ketoacidosis. She presented to the ED with normal vitals, grossly normal physical exam and labs were significant for beta-hydroxybutyrate of over 7 mmol/L (ref range <0.28), bicarbonate of 10 mmol/L (22 - 33), anion gap 25 (7 - 17), arterial pH 7.16 (7.33 - 7.43), serum glucose 111 (7.33 - 7.43). GAD-65 antibody titer was <5 IU/mL (< 5). She was diagnosed with euglycemic DKA, transferred to ICU and started on DKA protocol to which she responded very well. Second patient is A 65 Years old male with past medical history of CAD, HTN, HDL, history of PE/DVT and Type 2 DM was on insulin and jardiance, started ketodiet while continuing taking the jardiance and stopped taking his insulin because his sugars were controlled presented to the ED with abdominal pain, nausea and vomiting, had relatively normal vitals and benign physical exam, labs showed Bicarbonate of 9 mmol/L (22 - 33), anion gap of 31 (7 - 17), venous pH of 7.07 (7.33 - 7.43) glucose was 189 (7.33 - 7.43), beta-hydroxybutyrate of over 7.7 mmol/L (ref range <0.28), patient was admitted to the ICU and started on insulin on DKA protocol Conclusion: SGLT2 inhibitors may be associated with DKA due to their ketogenic effects secondary to enhanced lipolysis and increased glucagon to insulin ratio. although not expected, euglycemic DKA could be much more present in cases where there is predisposition to increase ketones generation w/without appropriate clearance eg. starvation, ketotic diet, AKI, etc. These should be monitored for and the patient needs to be educated about accordingly to prevent both adverse outcomes and potential decrease in drug use if not strongly indicated. also,It would be prudent for prescribing clinicians to advise patients to withhold potentially harming medications temporarily if they cannot maintain adequate oral intake.

Identification of ten novel SLC5A2 mutations and determination of the renal threshold for glucose excretion in Chinese patients with familial renal glucosuria

BackgroundFamilial renal glucosuria (FRG) is a rare renal tubular disorder characterized by isolated persistent glucosuria without both abnormal glucose metabolism and any signs of proximal tubular dysfunction. SLC5A2 gene mutations are responsible for most FRG cases. MethodsQuantitative test for 24-hour urine glucose and RTG were determined in 9 families (totaling 25 subjects). All coding regions, including intron-exon boundaries, were analyzed with PCR followed by direct sequence analysis. ResultsTen novel mutations were identified (c.331 T > C, p.W111R; c.374T>C, p.M125T; c.394C>T, p.R132C; c.612G>C, p.Q204H; c.829C>T, p.P277S; c.880G>A, p.D294N; c.1129G>A, p.G377S; c.1194C>A, p.F398L; c.1540C > T, p.P514S and c.1573C>T, p.H525Y). c.886(-10_-31)del that is specific to Chinese population was found in 5 out of 9 families, with a mutation rate of 28% (5/18). The compound heterozygotes presented with much lower RTG values (1.28 ± 0.10 mmol/L), compared with the carriers of heterozygous variants (5.14 ± 0.77 mmol/L) (p<0.01); c.886(-10_-31)del heterozygotes had significant lower RTG values than others (4.43 ± 0.37 vs 5.7 ± 0.51 mmol/L; p<0.01). ConclusionsTen novel SLC5A2 mutations are found and c.886(-10-31)del may be a hot spot mutation in Chinese population. Compound heterozygotes had much lower RTG values than simple heterozygotes. Mixed-meal tolerance test is a simple method for determining RTG in FRG patients.

The Relationship between Increases in Morning Spot Urinary Glucose Excretion and Decreases in HbA1C in Patients with Type 2 Diabetes After Taking an SGLT2 Inhibitor: A Retrospective, Longitudinal Study.

Introduction Sodium glucose co-transporter 2 (SGLT2) inhibitors increase urinary glucose excretion (UGE) by reducing the renal threshold for glucose excretion, which results in decreased serum glucose concentrations in patients with type 2 diabetes mellitus (T2D). However, no study to date has determined whether larger increases in UGE after SGLT2 inhibitor treatment correspond to larger reductions in glycated hemoglobin (HbA1C).MethodsWe enrolled participants who were newly prescribed an SGLT2 inhibitor (dapagliflozin 10 mg or ipragliflozin 50 mg, once daily) as an add-on therapy. Patients were tested for HbA1C and first morning spot urinary-creatinine and -glucose concentrations immediately prior to administration of the SGLT2 inhibitor and at a 12-week follow-up appointment. We investigated the relationship between increases in morning spot UGE and decreases in HbA1C.ResultsA total of 101 participants with T2D were enrolled. The median age and diabetes duration were 61.0 and 12.8 years, respectively, and the median HbA1C was 8.10%. SGLT2 inhibitors significantly lowered the HbA1C level, with a median change from baseline to week 12 of −0.60% (p < 0.001). Robust increases from baseline were seen for the morning spot urinary glucose-to-creatinine ratio (UGCR), with a median change at week 12 of 47.3 mg/mg. In the correlation analysis, the ∆HbA1C level showed a significant positive correlation with ∆morning spot UGCR (r = 0.395, p < 0.001). In other words, a greater reduction in HbA1C was correlated with a smaller increase in UGE. After adjusting for confounding variables, ∆HbA1C was significantly associated with ∆morning spot UGCR.ConclusionsAlthough SGLT2 inhibitor treatment leads to a reduced HbA1C level by augmenting UGE, larger increases in UGE do not correlate to larger reductions in HbA1C. This suggests that the increase in UGE might not be an indicator of the degree of reductions in blood glucose.Electronic supplementary materialThe online version of this article (doi:10.1007/s13300-017-0248-5) contains supplementary material, which is available to authorized users.

Characteristics and Impact Factors of Renal Threshold for Glucose Excretion in Patients with Type 2 Diabetes Mellitus.

Sodium glucose co-transporter 2 (SGLT-2) inhibitors are newly developed but promising medicine for type 2 diabetes. However, patients with a different renal threshold for glucose excretion (RTG) may have a different reaction to this medicine. Therefore, the objective of this study was to investigate the characteristics of RTG and its impact factors in patients with type 2 diabetes mellitus (T2DM). The clinical and laboratory data of 36 healthy individuals and 168 in-hospital patients with T2DM were collected and analyzed, RTG was calculated using blood glucose (BG) measured by dynamic BG monitoring, urinary glucose excretion (UGE) and estimated glomerular filtration rate (eGFR). The characteristics of RTG were investigated. The risk factors for high RTG were analyzed using non-conditional logistic regression analysis. Our results found that RTG of the T2DM group was higher than that of the healthy individuals (P < 0.05); and 22.22% from the healthy individuals group but 58.33% from the T2DM group had high RTG. Age, duration of diabetes, body mass index (BMI), and homeostasis model assessment insulin resistance index (HOMA-IR) were independently associated with high RTG (P < 0.05). Further stratified analysis revealed that RTG in T2DM patients increased with age, duration of diabetes, and BMI. In conclusion, RTG is increased in patients with T2DM, especially in those with longer diabetic duration, higher BMI, and those who are older. Therefore, these patients may be more sensitive to SGLT-2 inhibitors.

SGLT2 inhibition and ketoacidosis – should we be concerned?

SGLT2 inhibitors represent a novel class of oral glucose- lowering treatment that addresses some important unmet clinical needs in the treatment of type 2 diabetes, specifically weight reduction and a low propensity to cause hypoglycaemia. SGLT2 inhibition lowers the renal threshold for glucose excretion, resulting in renal glycosuria, a shift in substrate utilisation from carbohydrate to fat oxidation and hyperglucagonaemia; this poses a theoretical risk for ketoacidosis (including euglycaemic ketoacidosis) in the presence of other precipitating factors, especially reduction in insulin doses or low carbohydrate intake. There have been reports of several cases of ketoacidosis, mostly euglycaemic, and in people with type 1 or type 2 diabetes. Subsequent to this there were warnings from regulatory bodies (FDA and EMEA). In this article, we examine the reports of ketoacidosis associated with SGLT2 inhibition and try to explain the intrinsic pathophysiological mechanisms associated with this class of drugs which might contribute to ketoacidosis. The implications of these for clinical practice are summarised with key messages to health care providers.

Pharmacokinetics, Pharmacodynamics, and Safety of Canagliflozin in Japanese Patients with Type 2 Diabetes Mellitus.

IntroductionCanagliflozin is a sodium glucose co-transporter 2 inhibitor approved worldwide for the treatment of patients with type 2 diabetes mellitus (T2DM). The present study evaluated pharmacokinetics, pharmacodynamics, and safety of canagliflozin in Japanese patients with T2DM.MethodsCanagliflozin, at doses of 25, 100, 200, or 400 mg, was administered as a single dose and, after a washout of 1 day, in repeated doses for 14 consecutive days to 61 subjects in a randomized, double-blind, placebo-controlled study. Plasma concentrations of canagliflozin and urinary glucose excretion (UGE) were measured, and renal threshold for glucose excretion (RTG) was calculated. Safety was evaluated on the basis of adverse event (AE) reports, blood and urine laboratory parameters, and vital signs.ResultsPlasma canagliflozin maximum concentration and area under the concentration–time curve (AUC) values increased in a dose-dependent manner with the time to maximum concentration (t max) of 1.0 h and elimination half-life (t 1/2) of 10.22–13.26 h on Day 1. No significant changes in t max and t 1/2 were observed after multiple-dose administration. The linearity factors, as calculated from the ratios of AUC0–24h on Day 16 to AUC0–∞ on Day 1, were close to 1 in all canagliflozin groups. Canagliflozin increased UGE0–24h (80–110 g/day with canagliflozin ≥100 mg) and decreased RTG from the first day of treatment; these effects were sustained during the entire period of multiple administration. No significant AEs were noted. Urine volume was slightly increased on Day 1, but subsequent changes after repeated doses for 14 days were small. Urinary sodium tended to be higher in the early treatment period, whereas no particular change was observed in serum osmolality and hematocrit.ConclusionCanagliflozin increased UGE, decreased RTG, and was well tolerated throughout the entire period of multiple administrations in Japanese patients with T2DM.FundingMitsubishi Tanabe Pharma Corporation.Trial registration ClinicalTrials.gov#NCT00707954.Electronic supplementary materialThe online version of this article (doi:10.1007/s12325-015-0234-0) contains supplementary material, which is available to authorized users.

Determination of the Renal Threshold for Glucose Excretion in Familial Renal Glucosuria

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 (RT_G) 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 RT_G, according to a recently validated protocol. Results: In patients with homozygous mutations, RT_G 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) RT_G 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 RT_G and increases in UGE. Because determination of RT_G is not influenced by the filtered glucose load, the calculated RT_G values provide a more refined measure of the impact of mutations on renal glucose transport than can be obtained from UGE alone.

Effect of Hepatic or Renal Impairment on the Pharmacokinetics of Canagliflozin, a Sodium Glucose Co-transporter 2 Inhibitor

PurposeCanagliflozin is a sodium-glucose cotransporter 2 inhibitor approved for the treatment of type 2 diabetes mellitus (T2DM). Because T2DM is often associated with renal or hepatic impairment, understanding the effects of these comorbid conditions on the pharmacokinetics of canagliflozin, and further assessing its safety, in these special populations is essential. Two open-label studies evaluated the pharmacokinetics, pharmacodynamics (renal study only), and safety of canagliflozin in participants with hepatic or renal impairment. MethodsParticipants in the hepatic study (8 in each group) were categorized based on their Child-Pugh score (normal hepatic function, mild impairment [Child-Pugh score of 5 or 6], and moderate impairment [Child-Pugh score of 7–9]) and received a single oral dose of canagliflozin 300 mg. Participants in the renal study (8 in each group) were categorized based on their creatinine clearance (CLCR) (normal renal function [CLCR ≥80 mL/min]; mild [CLCR 50 to <80 mL/min], moderate [CLCR 30 to <50 mL/min], or severe [CLCR <30 mL/min] renal impairment; and end-stage renal disease [ESRD]) and received a single oral dose of canagliflozin 200 mg; the exception was those with ESRD, who received 1 dose postdialysis and 1 dose predialysis (10 days later). Canagliflozin’s pharmacokinetics and pharmacodynamics (urinary glucose excretion [UGE] and renal threshold for glucose excretion [RTG]) were assessed at predetermined time points. FindingsMean maximum plasma concentration (Cmax) and area under the plasma concentration-time curve from time zero to infinite (AUC)0–∞ values differed by <11% between the group with normal hepatic function and those with mild and moderate hepatic impairment. In the renal study, the mean Cmax values were 13%, 29%, and 29% higher and the mean AUC0–∞ values were 17%, 63%, and 50% higher in participants with mild, moderate, and severe renal impairment, respectively; values were similar in the ESRD group relative to the group with normal function, however. The amount of UGE declined as renal function decreased, whereas RTG was not suppressed to the same extent in the moderate to severe renal impairment groups (mean RTG, 93–97 mg/dL) compared with the mild impairment and normal function groups (mean RTG, 68–77 mg/dL). ImplicationsCanagliflozin’s pharmacokinetics were not affected by mild or moderate hepatic impairment. Systemic exposure to canagliflozin increased in the renal impairment groups relative to participants with normal renal function. Pharmacodynamic response to canagliflozin, measured by using UGE and RTG, declined with increasing severity of renal impairment. A single oral dose of canagliflozin was well tolerated by participants in both studies. ClinicalTrials.gov identifiers: NCT01186588 and NCT01759576.

Pharmacodynamic differences between canagliflozin and dapagliflozin: results of a randomized, double-blind, crossover study.

AimsTo compare the pharmacodynamic effects of the highest approved doses of the sodium glucose co‐transporter 2 (SGLT2) inhibitors canagliflozin and dapagliflozin on urinary glucose excretion (UGE), renal threshold for glucose excretion (RTG) and postprandial plasma glucose (PPG) excursion in healthy participants in a randomized, double‐blind, two‐period crossover study.MethodsIn each treatment period, participants (n = 54) received canagliflozin 300 mg or dapagliflozin 10 mg for 4 days (20 min before breakfast). A mixed‐meal tolerance test (600 kcal; 75 g glucose) was performed at baseline and on day 4 of each treatment period to assess changes in incremental PPG (PPGΔAUC 0–2 h). We measured 24‐h UGE and plasma glucose on day 4 to determine 24‐h mean RTG.ResultsCanagliflozin 300 mg and dapagliflozin 10 mg had similar effects on UGE and RTG for 4 h after dosing, but canagliflozin was associated with higher UGE and greater RTG reductions for the remainder of the day. Mean 24‐h UGE was ∼25% higher with canagliflozin than with dapagliflozin (51.4 vs. 40.8 g), and 24‐h mean RTG was ∼0.4 mmol/l (7 mg/dl) lower with canagliflozin than with dapagliflozin (3.79 vs. 4.17 mmol/l; p < 0.0001). Dapagliflozin had no effect on PPG excursion; canagliflozin delayed and reduced PPG excursion (between‐treatment difference in PPGΔAUC 0–2 h from baseline expressed as a percentage of baseline mean, −10.2%; p = 0.0122). Canagliflozin and dapagliflozin were generally well tolerated.ConclusionsIn healthy participants, canagliflozin 300 mg provided greater 24‐h UGE, a lower RTG and smaller PPG excursions than dapagliflozin 10 mg.

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

OBJECTIVETo 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 METHODSSubjects 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.RESULTSAt 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.CONCLUSIONSThe SGLT2 inhibitor dapagliflozin improves glycemic control in diabetic patients by reducing the TmG and threshold at which glucose is excreted in the urine.

Validation of a Novel Method for Determining the Renal Threshold for Glucose Excretion in Untreated and Canagliflozin-treated Subjects With Type 2 Diabetes Mellitus

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 also used to determine RTG during the MMTT. The methods were compared using the concordance correlation coefficient and geometric mean ratios.Results:In untreated and canagliflozin-treated subjects, the relationship between UGE rate and BG was well described by a threshold relationship. Good agreement was obtained between the MMTT-based and SHCP-derived RTG values. The concordance correlation coefficient (for all subjects) was 0.94; geometric mean ratios (90% confidence intervals) for RTG values (MMTT/SHCP) were 0.93 (0.89–0.96) in untreated subjects and 1.03 (0.78–1.37) in canagliflozin-treated subjects. Study procedures and treatments were generally well tolerated in untreated and canagliflozin-treated subjects.Conclusions:In both untreated and canagliflozin-treated subjects with T2DM, RTG can be accurately estimated from measured BG, UGE, and estimated glomerular filtration rates using an MMTT-based method.

Effect of canagliflozin on renal threshold for glucose, glycemia, and body weight in normal and diabetic animal models.

BackgroundCanagliflozin is a sodium glucose co-transporter (SGLT) 2 inhibitor in clinical development for the treatment of type 2 diabetes mellitus (T2DM).Methods 14C-alpha-methylglucoside uptake in Chinese hamster ovary-K cells expressing human, rat, or mouse SGLT2 or SGLT1; 3H-2-deoxy-d-glucose uptake in L6 myoblasts; and 2-electrode voltage clamp recording of oocytes expressing human SGLT3 were analyzed. Graded glucose infusions were performed to determine rate of urinary glucose excretion (UGE) at different blood glucose (BG) concentrations and the renal threshold for glucose excretion (RTG) in vehicle or canagliflozin-treated Zucker diabetic fatty (ZDF) rats. This study aimed to characterize the pharmacodynamic effects of canagliflozin in vitro and in preclinical models of T2DM and obesity.ResultsTreatment with canagliflozin 1 mg/kg lowered RTG from 415±12 mg/dl to 94±10 mg/dl in ZDF rats while maintaining a threshold relationship between BG and UGE with virtually no UGE observed when BG was below RTG. Canagliflozin dose-dependently decreased BG concentrations in db/db mice treated acutely. In ZDF rats treated for 4 weeks, canagliflozin decreased glycated hemoglobin (HbA1c) and improved measures of insulin secretion. In obese animal models, canagliflozin increased UGE and decreased BG, body weight gain, epididymal fat, liver weight, and the respiratory exchange ratio.ConclusionsCanagliflozin lowered RTG and increased UGE, improved glycemic control and beta-cell function in rodent models of T2DM, and reduced body weight gain in rodent models of obesity.

Canagliflozin improves glycaemic control over 28 days in subjects with type 2 diabetes not optimally controlled on insulin

Canagliflozin is a sodium-glucose co-transporter 2 (SGLT2) inhibitor that is being investigated for the treatment of type 2 diabetes mellitus (T2DM). This was a randomized, double-blind, placebo-controlled, parallel-group, 28-day study conducted at two sites, in 29 subjects with T2DM not optimally controlled on insulin and up to one oral antihyperglycaemic agent. Subjects were treated with canagliflozin 100 mg QD or 300 mg twice daily (BID) or placebo. Safety, tolerability, pharmacokinetic characteristics and pharmacodynamic effects of canagliflozin were examined. Glucose malabsorption following a 75-g oral glucose challenge was also examined. Canagliflozin pharmacokinetics were dose-dependent, and the elimination half-life ranged from 12 to 15 h. After 28 days, the renal threshold for glucose excretion was reduced; urinary glucose excretion was increased; and A1C, fasting plasma glucose and body weight decreased in subjects administered canagliflozin (A1C reductions: 0.19% with placebo, 0.73% with 100 mg QD, 0.92% with 300 mg BID; body weight changes: 0.03 kg increase with placebo, 0.73 kg reduction with 100 mg QD, 1.19 kg reduction with 300 mg BID). Glucose malabsorption was not observed with canagliflozin treatment. There were no deaths, serious adverse events or severe hypoglycaemic episodes. The incidence of adverse events was similar across groups. There were no clinically meaningful changes in routine laboratory safety tests, vital signs or electrocardiograms. In subjects receiving insulin and oral antihyperglycaemic therapy, canagliflozin was well tolerated without evidence for glucose malabsorption, had pharmacokinetic characteristics consistent with once-daily dosing, and improved glycaemic control.

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

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.

Renal Glucose Excretion and Tubular Reabsorption Rate Related to Blood Glucose in Subjects with Type 2 Diabetes with a Critical Reappraisal of the “Renal Glucose Threshold” Model

Until today a "renal threshold for glucose" is described in most medical textbooks. Notwithstanding, low glucose levels are detectable in urine even under euglycaemic conditions - a phenomenon which was observed already in 1904 and labelled as "basal glucosuria". We aimed to characterise renal glucose transport during various steady-state blood glucose levels. Twenty-two subjects with type 2 diabetes and normal renal function underwent two 5-period hyperglycaemic glucose-clamps with blood glucose target levels between 7.8 and 13.3 mmol x l(-1). A virtual renal threshold for glucose excretion (VRT (G)) was calculated for every subject as the highest blood glucose concentration during the glucose-clamps associated with a concomitant urinary glucose level of <2.8 mmol x l(-1). VRT (G) of subjects was classified as low, medium, and high. Each urine sample contained a detectable amount of glucose with a minimal urinary glucose concentration of 0.73 mmol x l(-1). Median VRT (G) was 11.0 mmol x l(-1), ranging from 7.8 and 12.1 mmol x l(-1). With increasing blood glucose renal glucose excretion increased in each subject - but varied considerably between subjects. For example, at a blood glucose concentration of 11 mmol x l(-1) renal glucose excretion ranged from 163 micromol x min(-1) to 25 micromol x min(-1) in subjects exhibiting a low to high VRT (G), thus showing a variability >factor 6. This study reinforces the rejection of the concept of a renal threshold for glucose. Instead, this study shows a substantial variability of renal glucose excretion between subjects with type 2 diabetes.

Renal glucose excretion as a function of blood glucose concentration in subjects with type 2 diabetes—results of a hyperglycaemic glucose clamp study

The purpose of this study was to investigate renal glucose excretion as a function of blood glucose concentration and to evaluate the within-subject variability and between-subject variability in subjects with type 2 diabetes. Twenty-two subjects with type 2 diabetes [age 58 (12) years, diabetes duration 7 (6) years, endogenous creatinine clearance 117 (38) ml min(-1) 1.73 m(-2); median (inter-quartile range, IQR)] underwent two five-period hyperglycaemic glucose clamp experiments at intervals of 7-21 days. Starting from an initial blood glucose level of 12.2 mmol l(-1), subsequent glucose clamp levels were chosen using an algorithm based on urinary glucose concentrations measured at the end of the preceding glucose clamp period. That is, blood glucose was either stepwise decreased or increased depending on whether urinary glucose concentration was above or below 11.1 mmol l(-1), respectively. As expected, increasing the blood glucose from 7.8 to 13.3 mmol l(-1) during the glucose clamps resulted in a steep increase of urinary glucose excretion from 0.06 to 0.77 mmol min(-1). With decreasing blood glucose, a measurable glucosuria persisted up to a blood glucose level of 7.8 mmol l(-1). When defining the (pseudo)threshold for renal glucose excretion (PRT(G)) as the highest blood glucose level during glucose clamps associated with a concomitant glucose concentration in urine of <2.8 mmol l(-1), median (IQR) PRT(G) was 11.0 (1.1) mmol l(-1). The within-subject variability of PRT(G), i.e. the difference between two assessments, was low, 0.1 (0.0) mmol l(-1) while the between-subject variability of PRT(G) was high, ranging from 7.7 to 12.2 mmol l(-1). Renal glucose excretion increases in a proportional manner with increasing blood glucose. When decreasing blood glucose to euglycaemic blood glucose levels, glucosuria persists so that the classical concept of a renal threshold for glucose excretion cannot be upheld in subjects with type 2 diabetes.

Urinary excretion of 1,5-anhydro-D-glucitol accompanying glucose excretion in diabetic patients.

The urinary excretion of 1,5-anhydro-D-glucitol, a pyranoid polyol, in humans was studied. The plasma of nondiabetic human subjects contained high concentrations of this polyol (greater than 110 mumol/l), and there was a tendency for the 24-h excretion of it to become more variable in direct proportion to its plasma concentration. In contrast, diabetic patients showed lower plasma concentrations of this polyol, and the variation in the 24-h excretion of 1,5-anhydro-D-glucitol was especially notable among the patients with an extremely low plasma concentration of the polyol. This diabetic group showed a statistically significant correlation (p less than 0.01), between the urinary 1,5-anhydro-D-glucitol and urinary glucose. This correlation was more markedly demonstrated during a 100-g oral glucose tolerance test: parallel changes were observed in the concentrations of 1,5-anhydro-D-glucitol and glucose in the urine collected every hour after the glucose load. These observations led to the proposal that low plasma concentration of this polyol, which is observed in diabetes mellitus, may be the result of a frequent and/or prolonged high blood glucose concentration beyond the renal threshold for glucose excretion.