Fotagliptin monotherapy with alogliptin as an active comparator in patients with uncontrolled type 2 diabetes mellitus: a randomized, multicenter, double-blind, placebo-controlled, phase 3 trial.

BACKGROUND: Dipeptidyl peptidase-4 inhibitors (DPP-4i) have become firmly established in treatment algorithms and national guidelines for improving glycemic control in type 2 diabetes mellitus (T2DM).To report the findings from a multicenter, randomized, double-blind, placebo-controlled phase 3 clinical trial, which was designed to assess the efficacy and safety of a novel DPP-4 inhibitor fotagliptin in treatment-naive patients with T2DM. METHODS: Patients with T2DM were randomized to receive fotagliptin (n = 230), alogliptin (n = 113) or placebo (n = 115) at a 2:1:1 ratio for 24 weeks of double-blind treatment period, followed by an open-label treatment period, making up a total of 52 weeks. The primary efficacy endpoint was to determine the superiority of fotagliptin over placebo in the change of HbA1c from baseline to Week 24. All serious or significant adverse events were recorded. RESULTS: After 24 weeks, mean decreases in HbA1c from baseline were -0.70% for fotagliptin, -0.72% for alogliptin and -0.26% for placebo. Estimated mean treatment differences in HbA1c were -0.44% (95% confidence interval [CI]: -0.62% to -0.27%) for fotagliptin versus placebo, and -0.46% (95% CI: -0.67% to -0.26%) for alogliptin versus placebo, and 0.02% (95%CI: -0.16% to 0.19%; upper limit of 95%CI < margin of 0.4%) for fotagliptin versus alogliptin. So fotagliptin was non-inferior to alogliptin. Compared with subjects with placebo (15.5%), significantly more patients with fotagliptin (37.0%) and alogliptin (35.5%) achieved HbA1c < 7.0% after 24 weeks of treatment. During the whole 52 weeks of treatment, the overall incidence of hypoglycemia was low for both of the fotagliptin and alogliptin groups (1.0% each). No drug-related serious adverse events were observed in any treatment group. CONCLUSIONS: In summary, the study demonstrated improvement in glycemic control and a favorable safety profile for fotagliptin in treatment-naive patients with T2DM. TRIAL REGISTRATION: ClinicalTrail.gov NCT05782192.

Effects of SIRT1 on Osteogenic Differentiation of Bone Marrow Mesenchymal Stem Cells in Type 2 Diabetic Patients.

BACKGROUND: Patients with type 2 diabetes mellitus (T2DM) are at high risk for osteoporosis. SIRT1 plays an important regulatory role in the occurrence and development of diabetes mellitus; however, it is still not clear whether SIRT1 is directly related to the osteogenic ability of bone marrow mesenchymal stem cells (BMSCs) in T2DM patients. METHODS: We obtained BMSCs from patients with T2DM and healthy volunteers to determine the effect of SIRT1 expression on the osteogenic capacity of BMSCs. As a result, SIRT1 expression in BMSCs in T2DM was significantly lower compared to healthy volunteers, but the proliferative capacity of BMSCs in the T2DM group was not significantly different from that of healthy volunteers. RESULTS: During osteogenic differentiation, the expression of SIRT1 in MSCs from T2DM patients was significantly decreased, and the osteogenic differentiation ability of MSCs from T2DM patients was significantly lower than healthy volunteers. After intervention with resveratrol, the expression of SIRT1 increased significantly, and the apoptotic rate of MSCs in T2DM patients decreased significantly. Moreover, resveratrol promoted osteoblast differentiation of MSCs. CONCLUSION: Our study confirmed that the expression of SIRT1 is directly related to the osteogenic potential of BMSCs in patients with T2DM. Resveratrol promoted the osteogenic differentiation of BMSCs by increasing the expression of SIRT1. The increased expression of SIRT1 significantly reduced BMSC apoptosis during osteogenic differentiation, which is one of the important mechanisms by which SIRT1 regulates the osteogenic ability of BMSCs. Our data also provide strong evidence that resveratrol may be used in the treatment of osteoporosis in patients with T2DM.

Effects of Type 2 Diabetic Serum on Proliferation and Osteogenic Differentiation of Mesenchymal Stem Cells.

Diabetic patients have an increased risk of osteoporosis-associated fractures. However, the results of most studies of the effects of diabetes on bone mass in patients with type 2 diabetes (T2DM) have been contradictory. To clarify these conflicting findings, we investigated the effects of diabetic serum on the proliferation and osteogenic differentiation of mesenchymal stem cells (MSCs). We used human sera from subjects with different levels of glycemic control to culture the MSCs and induce osteogenic differentiation. The rate of MSC proliferation differed when MSCs were cultured with sera from diabetic subjects with different levels of hyperglycemia. Hyperglycemic sera promoted MSC proliferation to some extent, but all the diabetic sera inhibited the differentiation of MSCs to osteoblasts. The effects of type 2 diabetic sera on the proliferation and osteogenic differentiation of MSCs are closely related to glycemic control. Our data demonstrate the importance of stratifying the study population according to glycemic control in clinical research into diabetic osteoporosis.

Expressions of Tumor Necrosis Factor alpha-induced Protein 3 and Mammary Serine Protease Inhibitor in Radiotherapy of Nasopharyngeal Carcinoma.

OBJECTIVE: To study the expressions of tumor necrosis factor alpha-induced protein 3(TNFAIP3) and mammary serine protease inhibitor (Maspin) in the radiotherapy of nasopharyngeal carcinoma and explore the differences in radiosensitivity and radioresistance,the relation with the occurrence and development of radioresistance. METHODS: The TNFAIP3 and Maspin mRNA expressions were detected by using TNFAIP3 and Maspin multi-point labeled DIG probes in situ hybridization. RESULTS: In radiosensitivity and radioresistance of nasopharyngeal carcinoma,the moderately and strongly positive TNFAIP3 mRNA expression rates were 27.50% and 48.33% (P=0.037), and the moderately and strongly positive Maspin mRNA expression rates were 67.50% and 46.67% (P=0.040). In the radioresistance of nasopharyngeal carcinoma,TNFAIP3 mRNA moderately and strongly positive expressions were positively correlated with TNM stage (P=0.005). In distant metastasis and no distant metastasis (70.00% and 37.50%, P=0.018), the expression rates had statistical significance. The Maspin mRNA moderately and strongly positive expressions were positively correlated with TNM stage (P=0.039) and T stage (P=0.021). In distant metastasis and no distant metastasis (65.00% and 37.50%, P=0.044), the expression rates had statistical significance. CONCLUSION: TNFAIP3 may be involved in the development of radioresistant nasopharyngeal carcinoma,and Maspin may be related with the invasion and metastasis of radioresistant nasopharyngeal carcinoma.

Effects of caloric restriction on SIRT1 expression and apoptosis of islet beta cells in type 2 diabetic rats.

Increasing evidence suggests that a restricted caloric intake extends the life span of mammals, and SIRT1 may play a key role in this process. To study the effects of caloric restriction on SIRT1 expression and apoptosis of islet beta cells in type 2 diabetic rats, we first induced a model of type 2 diabetes in rats with a low-dose of streptozotocin. Then, the rats were fed with a normal diet, high-fat diet or 60% caloric restriction, respectively. As a result, the apoptosis ratio of islet beta cells in diabetic rats was dramatically increased compared to the control group, and mRNA and protein expression of SIRT1 in islet beta cells were much lower than those of the control group. After caloric restriction for 1 month, the blood glucose and serum insulin of rats decreased. The mRNA and protein expression of SIRT1 in islet beta cells significantly increased; however, the apoptosis ratio of islet beta cells decreased remarkably. These data show that caloric restriction notably improves the sensitivity to insulin and significantly increases mRNA and protein expression of SIRT1 while decreasing the apoptosis ratio of islet beta cells in diabetic rats. Therefore, SIRT1 may play an important role in the apoptosis of islet beta cells of type 2 diabetes.

[Study on abnormal glucose and lipid metabolism among 771 in-patients with ischemic stroke].

OBJECTIVE: To study the epidemiological characteristics of abnormal glucose and lipid metabolism in in-patients with ischemic stroke. METHODS: A total number of 771 in-patients with ischemic stroke, hospitalized in the Department of Neurology/Endocrinology from Changzhou No. 2 Hospital from April 2007 to April 2008 were enrolled in this study. After identifying the condition of glucose metabolism, all diagnosis-undetermined patients received oral glucose tolerance test. RESULTS: Among in-patients with ischemic stroke, 41.8% of the patients were finally diagnosed as diabetes, with 23.4% classified as 'impaired glucose tolerance'. The prevalence of 'abnormal glucose metabolism' was 65.2% in total. If diabetes in the in-patients with ischemic stroke was diagnosed only by fast plasma glucose instead of oral glucose tolerance test, 58.5% diabetic patients would have been misdiagnosed. Abnormal lipid metabolism existed in inpatients with cerebral ischemic stroke were noticed. These abnormalities of lipid metabolism were mainly consisting of increased triglyceride and decreased HDL-C cholesterol. CONCLUSION: The majority of in-patients with ischemic stroke appeared to have had abnormal glucose and lipid metabolism. It seemed necessary to promptly and correctly diagnose these patients with abnormal glucose metabolism by oral glucose tolerance test to reduce the chances of developing the recurrence of stroke.

[Effects of calorie restriction on SIRT1 expression in liver of nonalcoholic fatty liver disease: experiment with rats].

OBJECTIVE: To investigate the molecular mechanisms of calorie restriction (CR) in treatment of nonalcoholic fatty liver disease (NAFLD). METHODS: 25 male Wistar rats were randomly divided into 2 groups: normal control group (NC, n = 7) fed with regular diet and high fat diet-NAFLD model group (HFM, n = 18) fed with high-fat diet. Two months later, the rats in Group HFM were further divided into 2 subgroups: continuous high-fat feeding group (HF, n = 9) and normal diet feeding with 60% calorie restriction group (CR, n = 9). The rats were sacrificed after 1 month calorie restriction. By the end of experiment, body weight (BW), visceral fat mass (VF), fasting plasma glucose (FPG), fasting serum insulin (FINS), blood lipids (BL), including total cholesterol (TC) and triglyceride (TG), and hepatoultrastructure changes were examined to evaluate the effect of different feeding protocols on the experimental animals. The mRNA expression of the longevity gene SIRT1 in the liver was detected by RT-PCR. Western blot analysis was performed to determine the expression of SIRT1 protein in each group. RESULTS: Electron microscopy showed that the rats in group HF displayed obviously abnormal hepatoultrastructure, and the ultramicropathology changes of liver cell were improved obviously in Group CR. The VF, FINS, FPG, TC, and TG of the Group HF were 15.1 g +/- 4.1 g, 29.22 mU/L +/- 7.28 mU/L, 6.2 mmol/L +/- 1.46 mmol/L, 2.61 mmol/L +/- 0.29 mmol/L, and 1.35 mmol/L +/- 0.21 mmol/L respectively, all significantly higher than those in Group NC (9.0 g +/- 0.4 g, 13.09 mU/L +/- 1.18 mU/L, 4.4 mmol/L +/- 0.57 mmol/L, 1.41 mmol/L +/- 0.28 mmol/L, and 0.67 mmol/L +/- 0.10 mmol/L respectively, all P < 0.01). The mRNA expression of SIRT1 in the liver of Group HF was significantly lower than that of Group NC (P < 0.05), and the mRNA expression of SIRT1 in the liver of Group CR was significantly higher than those of Group HF and Group NC (both P < 0.01). The protein expression of SIRT1 of Group HF was significantly lower than that of Group NC (P < 0.01), and that of Group CR was significantly higher than that of Group HF, however, still significantly lower than that of Group NC (both P < 0.01). The BW and VF, FINS, FPG, TC, and TG of Group CR were all significantly lower than those of Group HF (all P < 0.01). CONCLUSION: CR can reverse NAFLD significantly. The increased expression of SIRT1 in liver induced by CR may be an important molecular mechanism involved in the improvement of NAFLD by CR.

The expression of SIRT1 in nonalcoholic fatty liver disease induced by high-fat diet in rats.

OBJECTIVE: SIRT1 is an NAD(+)-dependent deacetylase and its enzymatic activity may be regulated by cellular energy. SIRT1 overexpression reduces the level of oxygen consumption, which is correlative with nonalcoholic fatty liver disease (NAFLD). To elucidate the role of SIRT1 on the development of NAFLD, we investigated the expression of SIRT1 in NAFLD induced by high-fat diet in rats and the effects of calorie restriction. METHODS: Thirty-one male Wistar rats were divided at random into four groups. The rats in the normal control group NC (n=7) and in the NAFLD model group HF (n=9) were fed ad libitum with normal chow and high-fat diet, respectively, for 3 months, the rats in the calorie restriction (CR) group HCR (n=9) were fed with a high-fat diet for 2 months and then 60% CR with normal chow for 1 month, and the rats in group CRH (n=6) were firstly fed with 60% CR with normal chow for 1 month and then fed a high-fat diet for 2 months. At the end of the experiment, some parameters and expressions of SIRT1 were detected. RESULTS: The rats in group HF displayed NAFLD. Compared with group NC, the expression of SIRT1 protein was significantly decreased (P<0.01). However, the lower body weight and visceral fat mass of rats in group HCR were showed. Compared with group HF, CR increased the expression of SIRT1 in liver significantly (P<0.01). Consequently, the ultramicropathology changes of NAFLD prominently improved in this group. Meanwhile, the rats in group CRH displayed higher expression of SIRT1 protein and very gentle pathology changes of NAFLD. CONCLUSION: The expression of SIRT1 is reduced significantly in NAFLD induced by high-fat diet in rats. CR increase-SIRT1 protein expression may be an important mechanism by which CR improves NAFLD.