Eiji Kurosaki

Effects of SGLT2 selective inhibitor ipragliflozin on hyperglycemia, hyperlipidemia, hepatic steatosis, oxidative stress, inflammation, and obesity in type 2 diabetic mice

The sodium-glucose cotransporter 2 (SGLT2) is responsible for most glucose reabsorption in the kidney and has been proposed as a novel therapeutic target for the treatment of type 2 diabetes. In the present study, the therapeutic effects of SGLT2 selective inhibitor ipragliflozin were examined in high-fat diet and streptozotocin-nicotinamide-induced type 2 diabetic mice which exhibit impaired insulin secretion, insulin resistance, hyperlipidemia, hepatic steatosis, and obesity. Single administration of ipragliflozin dose-dependently increased urinary glucose excretion, reduced blood glucose and plasma insulin levels, and improved glucose intolerance. Four-week repeated administration of ipragliflozin improved not only glucose tolerance, hyperglycemia, and hyperinsulinemia but also impaired insulin secretion, hyperlipidemia, hepatic steatosis, and obesity with a concomitant increase in urinary glucose excretion. In addition, ipragliflozin reduced plasma and liver levels of oxidative stress biomarkers (thiobarbituric acid reactive substances and protein carbonyl) and inflammatory markers (interleukin 6, tumor necrosis factor α, monocyte chemotactic protein-1, and c-reactive protein), and improved liver injury as assessed by plasma levels of aminotransferases. These results demonstrate that SGLT2 selective inhibitor ipragliflozin improves not only hyperglycemia but also diabetes/obesity-associated metabolic abnormalities in type 2 diabetic mice and suggest that ipragliflozin may be useful in treating type 2 diabetes with metabolic syndrome.

Ipragliflozin and other sodium―glucose cotransporter-2 (SGLT2) inhibitors in the treatment of type 2 diabetes: Preclinical and clinical data

Sodium-glucose cotransporter-2 (SGLT2) is expressed in the proximal tubules of the kidneys and plays a key role in renal glucose reabsorption. A novel class of antidiabetic medications, SGLT2-selective inhibitors attempt to improve glycemic control in diabetics by preventing glucose from being reabsorbed through SGLT2 and re-entering circulation. Ipragliflozin is an SGLT2 inhibitor in Phase 3 clinical development for the treatment of type 2 diabetes mellitus (T2DM). In this review, we summarize recent animal and human studies on ipragliflozin and other SGLT2 inhibitors including dapagliflozin, canagliflozin, empagliflozin, tofogliflozin, and luseogliflozin. These agents all show potent and selective SGLT2 inhibition in vitro and reduce blood glucose levels and HbA1c in both diabetic animal models and patients with T2DM. SGLT2 inhibitors offer several advantages over other classes of hypoglycemic agents. Due to their insulin-independent mode of action, SGLT2 inhibitors provide steady glucose control without major risk for hypoglycemia and may also reverse β-cell dysfunction and insulin resistance. Other favorable effects of SGLT2 inhibitors include a reduction in both body weight and blood pressure. SGLT2 inhibitors are safe and well tolerated and can easily be combined with other classes of antidiabetic medications to achieve tighter glycemic control. The long-term safety and efficacy of these agents are under evaluation.

SGLT2 selective inhibitor ipragliflozin reduces body fat mass by increasing fatty acid oxidation in high-fat diet-induced obese rats

Ipragliflozin is a novel and selective sodium-glucose cotransporter 2 (SGLT2) inhibitor that induces sustained increases in urinary glucose excretion by inhibiting renal glucose reabsorption and thereby exerting a subsequent antihyperglycemic effect. Here, we examined the effect of ipragliflozin on body weight in high-fat diet-induced (HFD) obese rats. Treatment of ipragliflozin (10mg/kg once daily) reduced body weight despite a slight increase in food intake. Dual-energy X-ray absorptiometry and computed tomography demonstrated that the reduction in body weight was accompanied by reduced visceral and subcutaneous fat masses but not lean mass or bone mineral content. Analysis of plasma and urinary parameters suggested the possibility that ipragliflozin enhanced lipolysis and fatty acid oxidation, and indirect calorimetry showed that ipragliflozin decreased the heat production rate from glucose but increased the rate from fat and lowered the respiratory exchange ratio. In conclusion, these data demonstrate that ipragliflozin-induced urinary glucose excretion specifically reduces fat mass with steady calorie loss by promoting the use of fatty acids instead of glucose as an energy source in HFD rats. By improving hyperglycemia and promoting weight reduction, ipragliflozin may prove useful in treating type 2 diabetes in obese individuals.

Discovery of Ipragliflozin (ASP1941): a novel C-glucoside with benzothiophene structure as a potent and selective sodium glucose co-transporter 2 (SGLT2) inhibitor for the treatment of type 2 diabetes mellitus.

A series of C-glucosides with various heteroaromatics has been synthesized and its inhibitory activity toward SGLTs was evaluated. Upon screening several compounds, the benzothiophene derivative (14a) was found to have potent inhibitory activity against SGLT2 and good selectivity versus SGLT1. Through further optimization of 14a, a novel benzothiophene derivative (14h; ipragliflozin, ASP1941) was discovered as a highly potent and selective SGLT2 inhibitor that reduced blood glucose levels in a dose-dependent manner in diabetic models KK-A(y) mice and STZ rats.

Effects of sodium-glucose cotransporter 2 selective inhibitor ipragliflozin on hyperglycaemia, oxidative stress, inflammation and liver injury in streptozotocin-induced type 1 diabetic rats.

Sodium‐glucose cotransporter (SGLT) 2 plays an important role in renal glucose reabsorption and has been highlighted as a therapeutic target for the treatment of diabetes. Here, we investigated the therapeutic effects of SGLT2 selective inhibitor ipragliflozin in type 1 diabetic rats.

The novel hypoglycemic agent YM440 normalizes hyperglycemia without changing body fat weight in diabetic db/db mice

To determine the relationship between hypoglycemic activity and body weight gain induced by insulin sensitizers, we compared the effects of thiazolidinedione analogs (troglitazone and pioglitazone) and the oxadiazolidinedione analog (Z)-1,4-bis4[(3,5-dioxo-1,2,4-oxadiazolidin-2-yl)methyl]phen oxy¿but-2-ene (YM440) in diabetic db/db mice. Oral treatment with YM440(100 mg/kg) for 28 days decreased the blood glucose concentration (control v YM440, 418 +/- 12 v243 +/- 44 mg/dL). The hypoglycemic activity of this agent was comparable to that of troglitazone (300 mg/kg) and pioglitazone (100 mg/kg). There were no changes in food intake among the groups. Troglitazone and pioglitazone, but not YM440, significantly increased body weight gain during treatment (control, 7.2 +/- 0.5 g; YM440, 7.5 +/- 0.8 g; troglitazone, 10.9 +/- 0.8 g; and pioglitazone, 14.5 +/- 1.1 g). To further assess whether the increase in body weight by troglitazone or pioglitazone was due to adipogenesis, the weight of intraabdominal fat tissue (epididymal, retroperitoneal, and perirenal) was determined. There were no differences in the total weight of visceral fat between the control and YM440 treatment (3.53 +/- 0.23 and 3.60 +/- 0.16 g). In contrast, troglitazone and pioglitazone significantly increased the fat weight (4.31 +/- 0.13 and 4.66 +/- 0.19 g). Thiazolidinediones are known as ligands for peroxisome proliferator-activated receptor gamma (PPARgamma), a nuclear receptor responsible for adipogenesis. Troglitazone and pioglitazone activated PPARgamma and increased triglyceride accumulation and mRNA expression of fatty acid-binding protein (FABP) in 3T3-L1 cells. However, YM440 had no effect on these indices for adipocyte differentiation. These results suggest that the mechanism is different for the hypoglycemic action of YM440 versus the thiazolidinediones. YM440 ameliorates hyperglycemia without changing PPARgamma activity, adipocyte differentiation, or fat weight. Thus, YM440 could be a useful hypoglycemic agent for the treatment of non-insulin-dependent diabetes mellitus (NIDDM) without affecting body weight.

Ipragliflozin, an SGLT2 inhibitor, exhibits a prophylactic effect on hepatic steatosis and fibrosis induced by choline-deficient l-amino acid-defined diet in rats

Ipragliflozin is a selective sodium glucose cotransporter 2 (SGLT2) inhibitor that increases urinary glucose excretion by inhibiting renal glucose reabsorption and thereby causes a subsequent antihyperglycemic effect. As nonalcoholic fatty liver disease (NAFLD), including nonalcoholic steatohepatitis (NASH), is closely linked to metabolic diseases such as obesity and diabetes, we investigated the effect of ipragliflozin on NAFLD in rats fed a choline-deficient l-amino acid-defined (CDAA) diet. Five weeks after starting the CDAA diet, rats exhibited hepatic triglyceride (TG) accumulation, fibrosis, and mild inflammation. Repeated oral administration of ipragliflozin (3mg/g, once daily for 5 weeks) prevented both hepatic TG accumulation (188 vs.290 mg/g tissue vehicle-treated group; P<0.001) and large lipid droplet formation. Further, ipragliflozin exerted a prophylactic effect on liver fibrosis, as indicated by a marked decrease in hydroxyproline content and fibrosis score. Pioglitazone, which is known to be effective on hepatic fibrosis in CDAA diet-fed rats as well as NASH patients with type 2 diabetes mellitus (T2DM), also exerted a mild prophylactic effect on fibrosis, but not on hepatic TG accumulation or inflammation. In conclusion, ipragliflozin prevented hepatic TG accumulation and fibrosis in CDAA-diet rats. These findings suggest the therapeutic potential of ipragliflozin for patients with NAFLD.

Characterization and comparison of sodium-glucose cotransporter 2 inhibitors in pharmacokinetics, pharmacodynamics, and pharmacologic effects.

The sodium-glucose cotransporter (SGLT) 2 offer a novel approach to treating type 2 diabetes by reducing hyperglycaemia via increased urinary glucose excretion. In the present study, the pharmacokinetic, pharmacodynamic, and pharmacologic properties of all six SGLT2 inhibitors commercially available in Japan were investigated and compared. Based on findings in normal and diabetic mice, the six drugs were classified into two categories, long-acting: ipragliflozin and dapagliflozin, and intermediate-acting: tofogliflozin, canagliflozin, empagliflozin, and luseogliflozin. Long-acting SGLT2 inhibitors exerted an antihyperglycemic effect with lower variability of blood glucose level via a long-lasting increase in urinary glucose excretion. In addition, ipragliflozin and luseogliflozin exhibited superiority over the others with respect to fast onset of pharmacological effect. Duration and onset of the pharmacologic effects seemed to be closely correlated with the pharmacokinetic properties of each SGLT2 inhibitor, particularly with respect to high distribution and long retention in the target organ, the kidney. While all six SGLT2 inhibitors were significantly effective in increasing urinary glucose excretion and reducing hyperglycemia, our findings suggest that variation in the quality of daily blood glucose control associated with duration and onset of pharmacologic effects of each SGLT2 inhibitor might cause slight differences in rates of improvement in type 2 diabetes.

Synthesis and biological evaluation of C-glucosides with azulene rings as selective SGLT2 inhibitors for the treatment of type 2 diabetes mellitus: discovery of YM543.

Here, a series of C-glucosides with azulene rings in the aglycon moiety was synthesized and the inhibitory activities toward hSGLT1 and hSGLT2 were evaluated. Starting from the azulene derivative 7 which had relatively good SGLT2 inhibitory activity, compound 8a which has a 3-[(azulen-2-yl)methyl]phenyl group was identified as a lead compound for further optimization. Introduction of a phenolic hydroxyl group onto the central benzene ring afforded a potent and selective SGLT2 inhibitor 8e, which reduced blood glucose levels in a dose-dependent manner in rodent diabetic models. A mono choline salt of 8e (YM543) was selected as a clinical candidate for use in treating type 2 diabetes mellitus.

Distinct Properties of Telmisartan on Agonistic Activities for Peroxisome Proliferator-Activated Receptor γ among Clinically Used Angiotensin II Receptor Blockers: Drug-Target Interaction Analyses

A proportion of angiotensin II type 1 receptor blockers (ARBs) improves glucose dyshomeostasis and insulin resistance in a clinical setting. Of these ARBs, telmisartan has the unique property of being a partial agonist for peroxisome proliferator-activated receptor γ (PPARγ). However, the detailed mechanism of how telmisartan acts on PPARγ and exerts its insulin-sensitizing effect is poorly understood. In this context, we investigated the agonistic activity of a variety of clinically available ARBs on PPARγ using isothermal titration calorimetry (ITC) and surface plasmon resonance (SPR) system. Based on physicochemical data, we then reevaluated the metabolically beneficial effects of telmisartan in cultured murine adipocytes. ITC and SPR assays demonstrated that telmisartan exhibited the highest affinity of the ARBs tested. Distribution coefficient and parallel artificial membrane permeability assays were used to assess lipophilicity and cell permeability, for which telmisartan exhibited the highest levels of both. We next examined the effect of each ARB on insulin-mediated glucose metabolism in 3T3-L1 preadipocytes. To investigate the impact on adipogenesis, 3T3-L1 preadipocytes were differentiated with each ARB in addition to standard inducers of differentiation for adipogenesis. Telmisartan dose-dependently facilitated adipogenesis and markedly augmented the mRNA expression of adipocyte fatty acid-binding protein (aP2), accompanied by an increase in the uptake of 2-deoxyglucose and protein expression of glucose transporter 4 (GLUT4). In contrast, other ARBs showed only marginal effects in these experiments. In accordance with its highest affinity of binding for PPARγ as well as the highest cell permeability, telmisartan superbly activates PPARγ among the ARBs tested, thereby providing a fresh avenue for treating hypertensive patients with metabolic derangement.