Renal Glucose Transport Research Articles

Sodium-Glucose Cotransporter Inhibitors: Effects on Renal and Intestinal Glucose Transport: From Bench to Bedside.

Type 2 diabetes is a chronic disease with disabling micro- and macrovascular complications that lead to excessive morbidity and premature mortality. It affects hundreds of millions of people and imposes an undue economic burden on populations across the world. Although insulin resistance and insulin secretory defects play a major role in the pathogenesis of hyperglycemia, several other metabolic defects contribute to the initiation/worsening of the diabetic state. Prominent among these is increased renal glucose reabsorption, which is maladaptive in patients with diabetes. Instead of an increase in renal glucose excretion, which could ameliorate hyperglycemia, there is an increase in renal glucose reabsorption, which helps sustain hyperglycemia in patients with diabetes. The sodium-glucose cotransporter (SGLT) 2 inhibitors are novel antidiabetes agents that inhibit renal glucose reabsorption and promote glucosuria, thereby leading to reductions in plasma glucose concentrations. In this article, we review the long journey from the discovery of the glucosuric agent phlorizin in the bark of the apple tree through the animal and human studies that led to the development of the current generation of SGLT2 inhibitors.

Extract of Woodfordia fruticosa flowers ameliorates hyperglycemia, oxidative stress and improves β-cell function in streptozotocin–nicotinamide induced diabetic rats

Ethnopharmacological relevanceThe art of Ayurveda and the traditional healing system in India have reflected the ethnomedicinal importance of the plant Woodfordia fruticosa Kurtz, which demonstrates its vast usage in the Ayurvedic preparations as well as in the management of diabetes by the traditional healers. Aims of studyThe study aimed to ascertain the antidiabetic potential of W. fruticosa flower methanolic extract (WF) on Streptozotocin (STZ)–nicotinamide-induced diabetic rat model. Materials and methodsDiabetes was induced in Sprague Dawley (SD) rats by STZ–nicotinamide and thereafter diabetic rats were treated with three different doses of WF (100, 200 and 400mg/kg body weight) respectively and glibenclamide as a positive control. Biochemical parameters such as blood glucose, serum insulin and C-peptide levels were measured with oxidative stress markers. Furthermore, histology of liver and pancreas was carried out to evaluate glycogen content and β-cell structures. Moreover, immunohistochemistry and western blot analysis were performed on kidney and pancreas tissues to determine renal Bcl-2, pancreatic insulin and glucose transporter (GLUT-2, 4) protein expression in all the experimental groups. ResultsThe acute toxicity study showed non-toxic nature of all the three doses of WF. Further, studies on diabetic rats exhibited anti-hyperglycemic effects by upregulating serum insulin and C-peptide levels. Similarly, WF shown to ameliorate oxidative stress by downregulating LPO levels and augmenting the antioxidant enzyme (ABTS). Furthermore, histopathological analysis demonstrate recovery in the structural degeneration of β-cells mass of pancreas tissue with increase in the liver glycogen content of the diabetic rats. Interestingly, protective nature of the extract was further revealed by the immunohistochemical study result which displayed upregulation in the insulin and renal Bcl-2 expression, the anti apoptosis protein. Moreover, western blot result have shown slight alteration in the GLUT-2 and GLUT-4 protein expression with the highest dose of WFc treatment, that might have stimulated glucose uptake in the pancreas and played an important role in attenuating the blood glucose levels. ConclusionThe overall study result have demonstrated the potential of WF in the management of diabetes and its related complications, thus warrants further investigation on its major compounds with in depth mechanistic studies at molecular level.

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.

In Memoriam

In Memoriam

Familial renal glycosuria and modifications of glucose renal excretion

Under physiological conditions, the kidneys contribute to glucose homoeostasis by producing glucose by gluconeogenesis and preventing glucose loss in urine. The glucose filtered by the glomeruli is completely reabsorbed in the renal proximal tubule. Renal gluconeogenesis produces 25% of the circulating glucose in the postabsorptive state, while the amount of glucose reabsorbed by the kidneys largely exceeds the quantity synthesized by kidney gluconeogenesis. Sodium-glucose cotransporter type 2 (SGLT-2) and glucose transporter 2 (GLUT2) carry out more than 90% of renal glucose uptake. In diabetes, both gluconeogenesis and renal glucose reabsorption are increased. The augmentation of glucose uptake in diabetes is due to the overexpression of renal glucose transporters SGLT-2 and GLUT2 in response to the increase in expression of transcription activator hepatic nuclear factor 1-alpha (HNF1α). The rise in glucose uptake contributes to hyperglycaemia and induces glomerular hyperfiltration by increasing sodium and water reabsorption in the proximal tubule that, in turn, modifies urine flux at the macula densa. SGLT-2 inhibitors improve glycaemic control and prevent renal hyperfiltration in diabetes. Loss of SGLT-2 transporter function is a benign state characterized by glycosuria. In contrast, mutations of other glucose transporters expressed in the kidney are responsible for severe disorders.

Efficacy, safety and regulatory status of SGLT2 inhibitors: focus on canagliflozin.

Prevalence of diabetes mellitus is inc6reasing, with a burden of 382 million patients worldwide at present (more than the entire US population). The International Diabetes Federation anticipates an increase up to 592 million patients by 2035. Another major problem arises from the fact that just 50% of patients with type 2 diabetes mellitus are at target glycaemic control with currently available medications. Therefore, a clear need for new therapies that aim to optimize glycaemic control becomes evident. Renal sodium-linked glucose transporter 2 inhibitors are new antidiabetic drugs with an insulin-independent mechanism of action. They pose one remarkable advantage compared with already established antidiabetics: increasing urinary glucose excretion without inducing hypoglycaemia, thereby promoting body weight reduction due to loss of ~300 kcal per day. This review focuses on canagliflozin, which was the first successful compound of this class to be approved by both the US Food and Drug Administration and the European Medicines Agency in 2013. Clinical trials showed promising results: enhancing glycaemic control was paralleled by reducing body weight and systolic and diastolic blood pressure. Nevertheless, some safety concerns remain, such as genital mycotic infections, urinary tract infections and cardiovascular risks in vulnerable patients, which will be closely monitored in several post-authorization safety studies.

Bile acid sequestrants activate novel signaling pathways in the kidney and prevent obesity‐induced renal disease (767.10)

Bile acid sequestrants (BAS) are orally administered nonabsorbable polymers that decrease serum cholesterol and serum glucose in patients and animal models with type 2 diabetes mellitus. The effects of BAS on renal dysfunction in obesity and insulin resistance or type 2 diabetes mellitus have not been studied. Our goal was to evaluate the effect of BAS on metabolic and renal parameters in diet induced obesity. Our studies were performed in C57BL/6J male mice fed a control low fat (LF) diet (10 kcal% fat) or high fat (HF) diet (60 kcal% fat). The diets were supplemented with a) no addition or b) 2% sevelamer a BAS. Treatment with BAS prevented HF diet induced body weight gain, improved fasting blood glucose and glucose tolerance, and prevented the increases in serum cholesterol as well as insulin and leptin levels in HF mice. BAS prevented the increase in urine albumin excretion and decreased the PAS staining in the kidney of HF mice. Treatment with BAS decreased the renal lipid accumulation as shown by oil red O staining. HF diet induced upregulation of profibrotic genes (TGF‐β, CTGF, and PAI‐1) and proinflammatory genes (MCP‐1, TLR2, and TLR4) in the kidney which were decreased by treatment with BAS. In addition BAS induced downregulation of extracellular matrix protein fibronectin and macrophage marker CD68 expression in the kidney. The beneficial effects of BAS were also associated with decreases in renal gluconeogenic gene expression (PEPCK and G6Pase) and renal glucose transporter (SGLT2). Treatment with BAS also and most notably increased renal expression of Nrf1, SIRT1, PGC‐1a,SIRT3, ERRa, that mediate mitochondrial biogenesis, MCAD and LCAD, that mediate fatty acid oxidation, and Nrf2, HO‐1, and SOD, that mediate anti‐oxidative stress. In summary, our study showed a novel renoprotective role for bile acid sequestrant treatment in mice with diet induced obesity, insulin and leptin resistance.Grant Funding Source: NIH, VA, Genzyme, Daiichi Sankyo

Dapagliflozin improves muscle insulin sensitivity but enhances endogenous glucose production

Chronic hyperglycemia impairs insulin action, resulting in glucotoxicity, which can be ameliorated in animal models by inducing glucosuria with renal glucose transport inhibitors. Here, we examined whether reduction of plasma glucose with a sodium-glucose cotransporter 2 (SGLT2) inhibitor could improve insulin-mediated tissue glucose disposal in patients with type 2 diabetes. Eighteen diabetic men were randomized to receive either dapagliflozin (n = 12) or placebo (n = 6) for 2 weeks. We measured insulin-mediated whole body glucose uptake and endogenous glucose production (EGP) at baseline and 2 weeks after treatment using the euglycemic hyperinsulinemic clamp technique. Dapagliflozin treatment induced glucosuria and markedly lowered fasting plasma glucose. Insulin-mediated tissue glucose disposal increased by approximately 18% after 2 weeks of dapagliflozin treatment, while placebo-treated subjects had no change in insulin sensitivity. Surprisingly, following dapagliflozin treatment, EGP increased substantially and was accompanied by an increase in fasting plasma glucagon concentration. Together, our data indicate that reduction of plasma glucose with an agent that works specifically on the kidney to induce glucosuria improves muscle insulin sensitivity. However, glucosuria induction following SGLT2 inhibition is associated with a paradoxical increase in EGP. These results provide support for the glucotoxicity hypothesis, which suggests that chronic hyperglycemia impairs insulin action in individuals with type 2 diabetes.

Changes in Renal Glucose Transporters in an Animal Model of Metabolic Syndrome

Considering the similarity between structural, hemodynamic, and functional changes of obesity-related renal disease and diabetic nephropathy, we hypothesized that renal glucose transporter changes occur in obesity as in diabetes. The aim of the work was to evaluate GLUT1 and GLUT2 in kidneys of an animal model of metabolic syndrome. Neonate spontaneously hypertensive rats (SHR), n=15/group, were treated with monosodium glutamate (5 mg/g) (MetS) for 9 days and compared with saline-treated Wistar-Kyoto (C) and SHR (H) rats. Lee index, systolic arterial pressure (SAP), glycemia, insulin resistance, triglycerides, and HDL cholesterol were evaluated at 3 and 6 months. Medullar GLUT1 and cortical GLUT2 were analyzed by Western blot. MetS vs. C and H rats had the highest Lee index (p<0.001) and insulin resistance (3-months C: 4.3±0.7, H: 3.9±0.9, MetS: 2.7±0.6; 6-months C: 4.2±0.6, H: 3.8±0.5, MetS: 2.4±0.6% · min⁻¹, p<0.001), similar glycemia, and the lowest HDL-cholesterol at 6-months (p<0.001). In the MetS and H rats, SAP was higher vs. C at 3-months (p<0.001) and 6-months (C: 151±15, H: 190±11, MetS: 185±13 mm Hg, p<0.001) of age. GLUT1 was ̴ 13× lower (p<0.001) at 3-months, reestablishing its content at 6-months in MetS group, while GLUT2 was 2× higher (p<0.001) in this group at 6-months of age. Renal GLUT1 and GLUT2 are modulated in kidney of rats with metabolic syndrome, where obesity, insulin resistance and hypertension coexist, despite normoglycemia. Like in diabetes, cortical GLUT2 overexpression may contribute to the development of kidney disease.

Pregnancy-Associated Polyuria in Familial Renal Glycosuria

A pregnant woman presented at gestational week 28 with loss of consciousness and profound polyuria. Further characterization revealed osmotic diuresis due to massive glycosuria without hyperglycemia. Glycosuria reduced substantially postpartum, from approximately 100 to approximately 30 g/1.73 m2 per day. DNA sequencing analysis of the SLC5A2 gene encoding the renal glucose transporter SGLT2 showed a homozygous frame-shift mutation (occurring after the glutamine at amino acid 168 and leading to premature termination of the protein at amino acid 186) diagnostic of familial renal glycosuria. Pregnant women with familial renal glycosuria can be at risk of profound polyuria during pregnancy due to the associated increase in glycosuria. These findings also have implications for the use of SGLT2 inhibitors in clinical practice.

Renal GLUT1 reduction depends on angiotensin-converting enzyme inhibition in diabetic hypertensive rats

AimsAngiotensin-converting enzyme (ACE) inhibitors are used in diabetic kidney disease to reduce systemic/intra-glomerular pressure. The objective of this study was to investigate whether reducing blood pressure (BP) could modulate renal glucose transporter expression, and urinary markers of diabetic nephropathy in diabetic hypertensive rats treated with ramipril or amlodipine. Main methodsDiabetes was induced in spontaneously-hypertensive rats (~210g) by streptozotocin (50mg/kg). Thirty days later, animals received ramipril 15μg/kg/day (R, n=10), or amlodipine 10mg/kg/day (A, n=8,) or water (C, n=10) by gavage. After 30-day treatment, body weight, glycaemia, urinary albumin and TGF-β1 (enzyme-linked immunosorbent assay) and BP (tail-cuff pressure method) were evaluated. Kidneys were removed for evaluation of renal cortex glucose transporters (Western blotting) and renal tissue ACE activity (fluorometric assay). Key findingsAfter treatments, body weight (p=0.77) and glycaemia (p=0.22) were similar among the groups. Systolic BP was similarly reduced (p<0.001) in A and R vs. C (172.4±3.2; 186.7±3.7 and 202.2±4.3mmHg; respectively). ACE activity (C: 0.903±0.086; A: 0.654±0.025, and R: 0.389±0.057mU/mg), albuminuria (C: 264.8±15.4; A: 140.8±13.5 and R: 102.8±6.7mg/24h), and renal cortex GLUT1 content (C: 46.81±4.54; A: 40.30±5.39 and R: 26.89±0.79AU) decreased only in R (p<0.001, p<0.05 and p<0.001; respectively). SignificanceWe concluded that the blockade of the renin–angiotensin system with ramipril reduced early markers of diabetic nephropathy, a phenomenon that cannot be specifically related to decreased BP levels.

First human dose-escalation study with remogliflozin etabonate, a selective inhibitor of the sodium-glucose transporter 2 (SGLT2), in healthy subjects and in subjects with type 2 diabetes mellitus

BackgroundRemogliflozin etabonate (RE) is the prodrug of remogliflozin, a selective inhibitor of the renal sodium-dependent glucose transporter 2 (SGLT2), which could increase urine glucose excretion (UGE) and lower plasma glucose in humans.MethodsThis double-blind, randomized, placebo-controlled, single-dose, dose-escalation, crossover study is the first human trial designed to evaluate safety, tolerability, pharmacokinetics (PK) and pharmacodynamics of RE. All subjects received single oral doses of either RE or placebo separated by approximately 2 week intervals. In Part A, 10 healthy subjects participated in 5 dosing periods where they received RE (20 mg, 50 mg, 150 mg, 500 mg, or 1000 mg) or placebo (4:1 active to placebo ratio per treatment period). In Part B, 6 subjects with type 2 diabetes mellitus (T2DM) participated in 3 dose periods where they received RE (50 mg and 500 mg) or placebo (2:1 active to placebo per treatment period). The study protocol was registered with the NIH clinical trials data base with identifier NCT01571661.ResultsRE was generally well-tolerated; there were no serious adverse events. In both populations, RE was rapidly absorbed and converted to remogliflozin (time to maximum plasma concentration [Cmax;Tmax] approximately 1 h). Generally, exposure to remogliflozin was proportional to the administered dose. RE was rapidly eliminated (mean T½ of ~25 min; mean plasma T½ for remogliflozin was 120 min) and was independent of dose. All subjects showed dose-dependent increases in 24-hour UGE, which plateaued at approximately 200 to 250 mmol glucose with RE doses ≥150 mg. In T2DM subjects, increased plasma glucose following OGTT was attenuated by RE in a drug-dependent fashion, but there were no clear trends in plasma insulin. There were no apparent effects of treatment on plasma or urine electrolytes.ConclusionsThe results support progression of RE as a potential treatment for T2DM.Trial registrationClinicalTrials.gov NCT01571661

Where are we now in diabetic research?

Diabetes along with obesity has emerged as a silent epidemic worldwide owing to sedentary lifestyle and high calorie diets. This is certainly the case in Korea, where diabetes and pre-diabetes (impaired fasting glucose) accounted for 10.1 and 19.9 % of the population aged over 30 years or older, respectively, in 2010 (Diabetes Fact Sheet in Korea 2012). Likewise, in the United States, diabetes accounted for 25.8 million children and adults, 8.3 % of the population in 2010 (National Diabetes Fact Sheet 2011, USA). The physical and economic burden of diabetes to both the patient and society are enormous. Current anti-diabetic drugs with different mode of action have limited effectiveness and tolerability, and diabetic patients under current treatment modality will progress to microand macro-vascular complications. The prevalence of diabetes is predicted to rise continuously, and more people will experience diabetic complications unless new and more effective therapeutic and preventive measures become available. A large body of information has accumulated and important progress has been made in the last decade in our understanding of molecular mechanisms involved in the development and progression of insulin resistance, insulin secretion (b-cell function), and diabetic complications. These include autophagy, endoplasmic reticulum (ER) stress, metabolic sensors, abnormalities in metabolites formation and transcriptional machinery associated with glucose/lipid toxicity, dysregulation of adipokines, and chronic low grade inflammation. In addition, the discovery of microRNAs (miRNAs), short single-stranded RNA molecules comprising about 1 % of the genome and regulating target mRNA translational repression or cleavage, has increased our understanding on the pathogenesis of diabetes and its complications. Considering that diabetes has a strong genetic predisposition, the availability of genome-wide association (GWA) and exome sequencing studies will certainly improve our insights on genetics of diabetes and its complications. It is true, however, that effective treatment of diabetes and prevention of diabetic complications remain elusive goals. For future direction of research in diabetes to achieve a more effective correction of intracellular metabolic errors through exploration of new therapeutic targets, it is appropriate that we review current status of research in diabetic research. This special issue starts from the review by Cheon (2013), which provides the latest information about the novel molecular targets of type 2 diabetes mellitus (T2DM) pathogenesis and current development status of new T2DM therapeutics (Cheon 2013). Particularly, it highlights new therapeutic approaches, including incretin-based therapy, renal tubular glucose transporter inhibitors, b-hydroxysteroid dehydrogenase 1 inhibitors, peroxisome proliferator-activated receptor modulators, regulators of glucose/ lipid metabolism, and anti-inflammatory therapies. The next series of reviews deal with novel pathophysiological mechanisms of T2DM as an intension to seek for the novel therapeutic strategy. The second article by Lee (2013) and colleagues provides reviews on recent findings related to the roles of miRNAs in T2DM (Park et al. 2013a). The M.-K. Kwak College of Pharmacy, The Catholic University of Korea, Gyeonggi-do, Bucheon, South Korea e-mail: mkwak@catholic.ac.kr

Regional gastrointestinal delivery of remogliflozin etabonate in humans

Remogliflozin etabonate (RE) is the prodrug of remogliflozin (R), an inhibitor of renal glucose transport designed to reduce blood glucose concentrations for the treatment of type 2 diabetes. This open-label, randomized, single-dose, four-way crossover study, (with one add-on arm) in eight healthy men evaluated the regional gastrointestinal absorption of RE, the systemic appearance of the active entity R, and an active metabolite, GSK279782. The InteliSite(®) Companion Capsule was used to administer a single dose of RE 100 mg to the mid-small intestine or cecum/colon. Oral administration of the IR tablet of RE showed similar bioavailability of R compared with small intestine delivery with both suspension and solution. The lowest bioavailability of remogliflozin was found with large intestine delivery and therefore not a suitable region for prodrug delivery. Although both lower permeability and decreased ester hydrolysis of remogliflozin etabonate in the colon can explain reduced plasma exposures of remogliflozin, the data suggest relatively limited remogliflozin etabonate hydrolysis in the colon and provides evidence for a diminishing gradient of esterase activity from small to large intestine.

Improved glycemic control in mice lacking Sglt1 and Sglt2

Sodium-glucose cotransporter 2 (SGLT2) is the major, and SGLT1 the minor, transporter responsible for renal glucose reabsorption. Increasing urinary glucose excretion (UGE) by selectively inhibiting SGLT2 improves glycemic control in diabetic patients. We generated Sglt1 and Sglt2 knockout (KO) mice, Sglt1/Sglt2 double-KO (DKO) mice, and wild-type (WT) littermates to study their relative glycemic control and to determine contributions of SGLT1 and SGLT2 to UGE. Relative to WTs, Sglt2 KOs had improved oral glucose tolerance and were resistant to streptozotocin-induced diabetes. Sglt1 KOs fed glucose-free high-fat diet (G-free HFD) had improved oral glucose tolerance accompanied by delayed intestinal glucose absorption and increased circulating glucagon-like peptide-1 (GLP-1), but had normal intraperitoneal glucose tolerance. On G-free HFD, Sglt2 KOs had 30%, Sglt1 KOs 2%, and WTs <1% of the UGE of DKOs. Consistent with their increased UGE, DKOs had lower fasting blood glucose and improved intraperitoneal glucose tolerance than Sglt2 KOs. In conclusion, 1) Sglt2 is the major renal glucose transporter, but Sglt1 reabsorbs 70% of filtered glucose if Sglt2 is absent; 2) mice lacking Sglt2 display improved glucose tolerance despite UGE that is 30% of maximum; 3) Sglt1 KO mice respond to oral glucose with increased circulating GLP-1; and 4) DKO mice have improved glycemic control over mice lacking Sglt2 alone. These data suggest that, in patients with type 2 diabetes, combining pharmacological SGLT2 inhibition with complete renal and/or partial intestinal SGLT1 inhibition may improve glycemic control over that achieved by SGLT2 inhibition alone.

Autocrine modulation of glucose transporter SGLT2 by IL-6 and TNF-α in LLC-PK1 cells

We determined in cultured kidney epithelial cells (LLC-PK(1)) the effects of high glucose, interleukin-6 (IL-6), and tumor necrosis factor-α (TNF-α) on mRNA and protein expression of the renal glucose transporters SGLT1 and SGLT2. Cultured monolayers were incubated with similar concentrations of IL-6 and TNF-α to those produced by LLC-PK(1) in the presence of 20 mM glucose. Confluent monolayers with either 5 (controls, C) or 20 mM glucose (high glucose, HG) were incubated in the presence of 5 mM glucose, 20 mM glucose, 10 pg/ml IL-6, or TNF-α alone or in combination. Separate groups with IL-6 and TNF-α were incubated with antibodies to their respective receptors. HG induced an increased SGLT1 mRNA at 48 h (p<0.05 vs. C) and protein expression in 120 h (p<0.05 vs. C). HG also induced an increased SGLT2 mRNA at 72 and 96 h (P<0.05 vs. C) and SGLT2 protein expression at 120 h (p<0.05 vs. C). In C, 10 pg/ml IL-6 or TNF-α did not modify SGLT1 mRNA (n.s vs. in the absence of cytokines). In contrast, cytokines induced an increased expression of SGLT1 protein at 120 h (p<0.05 vs. in the absence of cytokines), and SGLT2 mRNA and protein were increased at 96 and 120 h, respectively (p<0.05 vs. in absence of cytokines). No changes were observed when cells were incubated with cytokines and HG (n.s vs. C). In conclusion, this study showed that SGLT2 increased in the presence of IL-6 and TNF-α, indicating an autocrine modulation of the expression of this transporter by cytokines.

Remogliflozin etabonate, a selective inhibitor of the sodium‐dependent transporter 2 reduces serum glucose in type 2 diabetes mellitus patients

Remogliflozin etabonate (RE) is the pro-drug of remogliflozin (R), a selective inhibitor of renal sodium-dependent glucose transporter 2 (SGLT2) that improves glucose control via enhanced urinary glucose excretion (UGE). This study evaluated the safety, tolerability, pharmacokinetics and pharmacodynamics of repeated doses of RE in subjects with type 2 diabetes mellitus (T2DM). In a double-blinded, randomized, placebo-controlled trial, subjects who were drug-naïve or had metformin discontinued received RE [100 mg BID (n = 9), 1000 mg QD (n = 9), 1000 mg BID (n = 9)], or placebo (n = 8) for 12 days. Safety parameters were assessed, including urine studies to evaluate renal function. Plasma concentrations of RE and metabolites were measured with the first dose and at steady state. RE effects on glucose levels were assessed with fasting glucose concentrations, frequently sampled 24-h glucose profiles and oral glucose tolerance tests. No significant laboratory abnormalities or safety events were reported; the most frequent adverse events were headache and flatulence. Plasma exposure to RE and R were proportional to administered dose with negligible accumulation. Mean 24-h UGE increased in RE treatment groups. Compared with the placebo group, 24-h mean (95% CI) changes in plasma glucose were -1.2 (-2.2 to -0.3) (100 mg BID), -0.8 (-1.7 to 0.2) (1000 mg QD) and -1.7 (-2.7 to -0.8) mmol/l (1000 mg BID). Administration of RE for 12 days is well-tolerated and results in clinically meaningful improvements in plasma glucose, accompanied by changes in body weight and blood pressure in subjects with T2DM.

Pharmacokinetic and Pharmacodynamic Modeling of the Effect of an Sodium-Glucose Cotransporter Inhibitor, Phlorizin, on Renal Glucose Transport in Rats

A pharmacokinetic and pharmacodynamic (PK-PD) model for the inhibitory effect of sodium-glucose cotransporter (SGLT) inhibitors on renal glucose reabsorption was developed to predict in vivo efficacy. First, using the relationship between renal glucose clearance and plasma glucose level in rats and both the glucose affinity and transport capacity obtained from in vitro vesicle experiments, a pharmacodynamic model analysis was performed based on a nonlinear parallel tube model to express the renal glucose transport mediated by SGLT1 and SGLT2. This model suitably expressed the relationship between plasma glucose level and renal glucose excretion. A PK-PD model was developed next to analyze the inhibitory effect of phlorizin on renal glucose reabsorption. The PK-PD model analysis was performed using averaged concentrations of both the drug and glucose in plasma and the corresponding renal glucose clearance. The model suitably expressed the concentration-dependent inhibitory effect of phlorizin on renal glucose reabsorption. The in vivo inhibition constants of phlorizin for SGLT in rats were estimated to be 67 nM for SGLT1 and 252 nM for SGLT2, which are similar to the in vitro data reported previously. This suggests that the in vivo efficacy of SGLT inhibitors could be predicted from an in vitro study based on the present PK-PD model. The present model is based on physiological and biochemical parameters and, therefore, would be helpful in understanding individual differences in the efficacy of an SGLT inhibitor.

Protective effects of cortex fraxini coumarines against oxonate-induced hyperuricemia and renal dysfunction in mice

The aim of the present study was to investigate the effects of cortex fraxini coumarines esculetin, esculin, fraxetin and fraxin on renal dysfunction and expression abnormality of renal organic ion transporters in hyperuricemic animals. Mice were orally given 250 mg/kg oxonate for seven consecutive days to induce hyperuricemia and renal dysfunction. After 1 h of oxonate induction daily, animals were orally treated with esculetin, esculin, fraxetin and fraxin at 20 and 40 mg/kg, respectively. Esculetin, esculin, fraxetin and fraxin significantly decreased serum urate, creatinine and blood urea nitrogen levels and increased urine urate and creatinine excretion in hyperuricemic mice. Esculetin and esculin up-regulated expressions of renal organic anion transporter 1 (mOAT1), organic cation and carnitine transporters (mOCT1-2 and mOCTN1-2), but failed to affect renal glucose transporter 9 (mGLUT9) and urate transporter 1 (mURAT1) in this model. Fraxetin specifically inhibited renal mURAT1, while fraxin extensively interacted with renal mGLUT9, mURAT1, mOAT1 and mOCT1 in hyperuricemic mice. Furthermore, esculetin, fraxetin and fraxin increased mABCG2 mRNA expression and decreased its protein levels in renal apical membrane in hyperuricemic mice. These results indicate that esculetin and esculin have beneficial effects on hyperuricemia and renal dysfunction, resulting in restoration of mOAT1, mOCT1-2 and mOCTN1-2, and fraxetin and fraxin enhance urate excretion partly by inhibiting mURAT1 or mGLUT9 in kidney of hyperuricemic mice. Regulation of mABCG2 by cortex fraxini coumarines may be partly contributed to their beneficial actions. This study provides an evidence to support clinical therapeutic effects of cortex fraxini coumarines on hyperuricemia with renal dysfunction.

Dapagliflozin: A Once-Daily Oral Therapy Sodium-Glucose Cotransporter-2 Inhibitor for the Treatment of Adult Patients with Type 2 Diabetes

The induction of glycosuria using phlorizin, a nonselective inhibitor of renal and intestinal transport was well recognised to lower glucose levels and induce calorie loss in animal models of diabetes. Phlorizin and other similar molecules however were not suitable for clinical use due to adverse effects of non selective inhibition of extra-renal glucose transport system. More recent understanding of the physiology of renal glucose transport system and increased knowledge of rare genetic syndromes of renal glycosuria has resulted in the development of drugs that selectively inhibit the Sodium Glucose Transporter-2 (SGLT2). Among the various agents currently being developed within this drug class, dapagliflozin is the most advanced in clinical development. This article discusses the basic physiology of the SGLT2 transporter system, pharmacokinetics and pharmacodynamic information of dapagliflozin, its efficacy in lowering HbA1c and weight as well as its safety and adverse effects profile. This is discussed based on evidence derived from clinical trials involving a spectrum of patients with diabetes, from drug naïve to individuals already on insulin therapy.