Ryoko Nagaishi

Contributing factors related to efficacy of the dipeptidyl peptidase-4 inhibitor sitagliptin in Japanese patients with type 2 diabetes

Patients’ characteristics related to efficacy of sitagliptin were examined in 345 Japanese individuals with inadequately controlled type 2 diabetes whose baseline characteristics are shown in Table 1. Patients received sitagliptin 50 mg/day for 24 weeks in addition to their existing diet therapy and other medications. We treated patients with sitagliptin at a dose of 50 mg, the standard dose in Japan, because a previous study reported that HbA1c reduction by sitagliptin was not different when the drug was given at this dose versus at doses 50 mg in Japanese patients with type 2 diabetes [1]. The primary endpoint

Exendin-4, a GLP-1 receptor agonist, attenuates prostate cancer growth.

Recently, pleiotropic benefits of incretin therapy beyond glycemic control have been reported. Although cancer is one of the main causes of death in diabetic patients, few reports describe the anticancer effects of incretin. Here, we examined the effect of the incretin drug exendin (Ex)-4, a GLP-1 receptor (GLP-1R) agonist, on prostate cancer. In human prostate cancer tissue obtained from patients after they had undergone radical prostatectomy, GLP-1R expression colocalized with P504S, a marker of prostate cancer. In in vitro experiments, Ex-4 significantly decreased the proliferation of the prostate cancer cell lines LNCap, PC3, and DU145, but not that of ALVA-41. This antiproliferative effect depended on GLP-1R expression. In accordance with the abundant expression of GLP-1R in LNCap cells, a GLP-1R antagonist or GLP-1R knockdown with small interfering RNA abolished the inhibitory effect of Ex-4 on cell proliferation. Although Ex-4 had no effect on either androgen receptor activation or apoptosis, it decreased extracellular signal–regulated kinase (ERK)-mitogen-activated protein kinase (MAPK) phosphorylation in LNCap cells. Importantly, Ex-4 attenuated in vivo prostate cancer growth induced by transplantation of LNCap cells into athymic mice and significantly reduced the tumor expression of P504S, Ki67, and phosphorylated ERK-MAPK. These data suggest that Ex-4 attenuates prostate cancer growth through the inhibition of ERK-MAPK activation.

Dipeptidyl peptidase-4 inhibitor linagliptin attenuates neointima formation after vascular injury

BackgroundRecently, glucagon-like peptide-1 (GLP-1)-based therapy, including dipeptidyl peptidase-4 (DPP-4) inhibitors and GLP-1 receptor agonists, has emerged as one of the most popular anti-diabetic therapies. Furthermore, GLP-1-based therapy has attracted increased attention not only for its glucose-lowering ability, but also for its potential as a tissue-protective therapy. In this study, we investigated the vascular-protective effect of the DPP-4 inhibitor, linagliptin, using vascular smooth muscle cells (VSMCs).MethodsSix-week-old male C57BL/6 mice were divided into control (n =19) and linagliptin (3 mg/kg/day, n =20) treated groups. Endothelial denudation injuries were induced in the femoral artery at 8 weeks of age, followed by evaluation of neointima formation at 12 weeks. To evaluate cell proliferation of rat aortic smooth muscle cells, a bromodeoxyuridine (BrdU) incorporation assay was performed.ResultsLinagliptin treatment reduced vascular injury-induced neointima formation, compared with controls (p <0.05). In these non-diabetic mice, the body weight and blood glucose levels did not change after treatment with linagliptin. Linagliptin caused an approximately 1.5-fold increase in serum active GLP-1 concentration, compared with controls. In addition, the vascular injury-induced increase in the oxidative stress marker, urinary 8-OHdG, was attenuated by linagliptin treatment, though this attenuation was not statistically significant (p =0.064). Moreover, linagliptin did not change the serum stromal cell-derived factor-1α (SDF-1α) or the serum platelet-derived growth factor (PDGF) concentration. However, linagliptin significantly reduced in vitro VSMC proliferation.ConclusionLinagliptin attenuates neointima formation after vascular injury and VSMC proliferation beyond the glucose-lowering effect.

The efficacy of incretin therapy in patients with type 2 diabetes undergoing hemodialysis

BackgroundAlthough incretin therapy is clinically available in patients with type 2 diabetes undergoing hemodialysis, no study has yet examined whether incretin therapy is capable of maintaining glycemic control in this group of patients when switched from insulin therapy. In this study, we examined the efficacy of incretin therapy in patients with insulin-treated type 2 diabetes undergoing hemodialysis.MethodsTen type 2 diabetic patients undergoing hemodialysis received daily 0.3 mg liraglutide, 50 mg vildagliptin, and 6.25 mg alogliptin switched from insulin therapy on both the day of hemodialysis and the non-hemodialysis day. Blood glucose level was monitored by continuous glucose monitoring. After blood glucose control by insulin, patients were treated with three types of incretin therapy in a randomized crossover manner, with continuous glucose monitoring performed for each treatment.ResultsDuring treatment with incretin therapies, severe hyperglycemia and ketosis were not observed in any patients. Maximum blood glucose and mean blood glucose on the day of hemodialysis were significantly lower after treatment with liraglutide compared with treatment with alogliptin (p < 0.05), but not with vildagliptin. The standard deviation value, a marker of glucose fluctuation, on the non-hemodialysis day was significantly lower after treatment with liraglutide compared with treatment with insulin and alogliptin (p < 0.05), but not with vildagliptin. Furthermore, the duration of hyperglycemia was significantly shorter after treatment with liraglutide on both the hemodialysis and non-hemodialysis days compared with treatment with alogliptin (p < 0.05), but not with vildagliptin.ConclusionsThe data presented here suggest that patients with type 2 diabetes undergoing hemodialysis and insulin therapy could be treated with incretin therapy in some cases.

Rapid Improvement of Blood Glucose Level after Prosthetic Mandibular Advancement in a Patient with Diabetes Mellitus and Obstructive Sleep Apnea

Introduction: Obstructive Sleep Apnea Syndrome (OSAS) is often associated with impaired glucose metabolism. However, the effects of Prosthetic Mandibular Advancement (PMA) on blood glucose levels and insulin resistance remain unclear. Therefore, we assessed the immediate effect of PMA on glycemic control measured using a Continuous Glucose Monitoring System (CGMS) in a patient with Type 2 Diabetes Mellitus (T2DM) and OSAS. Case presentation: A 77-year-old Japanese woman with T2DM was diagnosed with OSAS with a Respiratory Disturbance Index (RDI) of 39.3. Because the patient did not accept Continuous Positive Airway Pressure (CPAP) therapy, she wore a PMA that advanced the mandible 7 mm forward. Overnight sleep apnea monitoring and CGM were performed before and after wearing the PMA. PMA induced a marked reduction in RDI from 39.3 to 12.8, an increase in the minimum hemoglobin saturation from 78.0% to 87.0%, and a decrease in the number of episodes of oxygen desaturation of >4% below baseline in during the bedtime from 31.3 /h to 12.1 /h. The mean glucose level markedly improved with PMA from 126.1 to 100.5 mg/dL. Conclusion: The patient with showed improvement in RDI and glucose levels after wearing the PMA overnight. To our knowledge, this is the first case of a patient with OSAS and T2DM showing a beneficial effect of PMA on rapid glycemic control. CGMS may greatly help to promote compliance with the treatment of OSAS in patients with T2DM.