BACKGROUND Early diabetic nephropathy(DN)is a complication of diabetes mellitus.It mainly affects kidney microvessels and glomerular function,and its timely and effective treatment is critical for early DN.However,the...BACKGROUND Early diabetic nephropathy(DN)is a complication of diabetes mellitus.It mainly affects kidney microvessels and glomerular function,and its timely and effective treatment is critical for early DN.However,the effects of treatments comprising simple Western medicine are not optimal.With the promotion and implementation of integrated Chinese and western medicine treatments,remarkable results have been achieved for many diseases.To this end,we explored the clinical efficacy of integrated traditional Chinese and western medicines for the treatment of early DN.AIM To investigate the effect of sitagliptin tablets combined with Yiqi yangyin huoxue decoction on clinical efficacy and hemorheology in patients with early DN.METHODS Through a retrospective analysis,123 patients with early DN were admitted to the endocrinology clinic of the Changzhou NO.7 People’s Hospital from January 2021 to October 2022 and were selected as study subjects.After rigorous screening,100 patients with early DN were enrolled.The control group(CG,n=50)and the observation group(OG,n=50)were divided according to the treatment method.The CG were treated with sitagliptin,and the OG were treated with sitagliptin plus the Yiqi yangyin huoxue decoction.Both groups were treated for 3 mo.For both groups,the baseline data and clinical efficacy were compared,and changes in blood glucose levels,lipid levels,renal function,and hematological indicators before(T0)and after(T1)treatment were assessed.RESULTS The total effective rate for the OG was 94.00%and that of the CG was 80.00%(P<0.05).After treatment(T1),the levels of fasting blood glucose,2 h postprandial glucose,total cholesterol,triacylglycerol,and low-density lipoprotein cholesterol in OG patients were obviously lower than those in the CG(P<0.05),and cystatin C,homocysteine,urinary microalbumin,and blood creatinine values in OG patients were also obviously lower than those in the CG(P<0.05);erythrocyte deposition,plasma viscosity,whole blood high shear viscosity,and whole blood low shear viscosity were markedly lower in OG patients than in the CG(P<0.05).CONCLUSION Sitagliptin combined with Yiqi yangyin huoxue decoction has a remarkable effect when used to treat patients with early DN.Further,it is helpful in improving hemorheological indices and controlling disease progression.展开更多
AIMTo evaluate the effect of sitagliptin vs placebo on histologic and non-histologic parameters of non-alcoholic steatohepatitis (NASH).METHODSTwelve patients with biopsy-proven NASH were randomized to sitagliptin (10...AIMTo evaluate the effect of sitagliptin vs placebo on histologic and non-histologic parameters of non-alcoholic steatohepatitis (NASH).METHODSTwelve patients with biopsy-proven NASH were randomized to sitagliptin (100 mg daily) (n = 6) or placebo (n = 6) for 24 wk. The primary outcome was improvement in liver fibrosis after 24 wk. Secondary outcomes included evaluation of changes in NAFLD activity score (NAS), individual components of NAS (hepatocyte ballooning, lobular inflammation, and steatosis), glycemic control and insulin resistance [including measurements of glycated hemoglobin (HbA1C) and adipocytokines], lipid profile including free fatty acids, adipose distribution measured using magnetic resonance imaging (MRI), and thrombosis markers (platelet aggregation and plasminogen activator inhibitor 1 levels). We also sought to determine the correlation between changes in hepatic fat fraction (%) [as measured using the Iterative Decomposition of water and fat with Echo Asymmetry and Least-squares estimation (IDEAL) MRI technique] and changes in hepatic steatosis on liver biopsy.RESULTSSitagliptin was not significantly better than placebo at reducing liver fibrosis score as measured on liver biopsy (mean difference between sitagliptin and placebo arms, 0.40, P = 0.82). There were no significant improvements evident with the use of sitagliptin vs placebo for the secondary histologic outcomes of NAS total score as well as for the individual components of NAS. Compared to baseline, those patients who received sitagliptin demonstrated improved HbA1C (6.7% ± 0.4% vs 7.9% ± 1.0%, P = 0.02), and trended towards improved adiponectin levels (4.7 ± 3.5 μg/mL vs 3.9 ± 2.7 μg/mL, P = 0.06) and triglyceride levels (1.26 ± 0.43 mmol/L vs 2.80 ± 1.64 mmol/L, P = 0.08). However, when compared with placebo, sitagliptin did not cause a statistically significant improvement in HbA1C (mean difference, -0.7%, P = 0.19) nor triglyceride levels (mean difference -1.10 mmol/L, P = 0.19) but did trend towards improved adiponectin levels only (mean difference, 0.60 μg/mL, P = 0.095). No significant changes in anthropometrics, liver enzymes, other adipocytokines, lipid profile, thrombosis parameters, or adipose distribution were demonstrated. The MRI IDEAL procedure correlated well with steatosis scores obtained on liver biopsy in both groups at baseline and post-treatment, and the Spearman correlation coefficients ranged from r = 0.819 (baseline) to r = 0.878 (post-treatment), P = 0.002.CONCLUSIONSitagliptin does not improve fibrosis score or NAS after 24 wk of therapy. The MRI IDEAL technique may be useful for non-invasive measurement of hepatic steatosis.展开更多
Objective:To study the effect of sitagliptin on adipocytokines expression in diabetic rats and its molecular mechanism.Methods:Male SD rats were chosen and randomly divided into NC group,T2DM group,SP group and SP+LY ...Objective:To study the effect of sitagliptin on adipocytokines expression in diabetic rats and its molecular mechanism.Methods:Male SD rats were chosen and randomly divided into NC group,T2DM group,SP group and SP+LY group.NC group received conventional breeding,T2DM group,SP group and SP+LY group received intraperitoneal injection of streptozotocin after 12 weeks of high-fat diet to establish diabetes animal model,SP group received sitagliptin intervention and SP+LY group received sitagliptin combined with PI3 K inhibitor LY294002 intervention.6 weeks after the intervention,serum was collected to determine the levels of biochemical indexes and adipocytokines,and visceral adipose tissue was collected to determine expression levels of adipocytokines.Results:Serum TC,TG,LDL-C,FBG,FINS,Leptin and Chemerin levels as well as HOMA-IR of T2DM group were higher than those of NC group,and HDL-C,Adiponectin and Omentin-1 levels were significantly lower than those of NC group; serum TC,TG,LDL-C,FBG,FINS,Leptin and Chemerin levels as well as HOMA-IR of SP group were lower than those of T2DM group,and HDL-C,Adiponectin and Omentin-1 levels were significantly higher than those of T2DM group; Leptin and Chemerin levels in serum and visceral adipose tissue of SP+LY group were higher than those of SP group while Adiponectin and Omentin-1 levels were significantly lower than those of SP group.Conclusion:Sitagliptin can regulate the expression of adipocytokines in adipose tissue of diabetic rats through PI3K-AKT pathway.展开更多
AIM: To assess the effects of sitagliptin and nateglinide on lipid metabolism. METHODS: In a parallel group comparative open trial, patients with type 2 diabetes mellitus under treatment at the Japanese Red Cross Medi...AIM: To assess the effects of sitagliptin and nateglinide on lipid metabolism. METHODS: In a parallel group comparative open trial, patients with type 2 diabetes mellitus under treatment at the Japanese Red Cross Medical Center were randomly assigned to receive either sitagliptin (50 mg once daily) or nateglinide (90 mg three times daily before meals). Eligible patients met the following criteria: age ≥ 20 years; hemoglobin A 1c (HbA 1c ) > 6.5% despite diet and exercise; HbA 1c between 6.5% and 8.0%; fasting glucose < 7.77 mmol/L; diet and exercise therapy for more than 3 mo; and ability to read and understand the information for written informed consent. Exclusion criteria were contraindications to sitagliptin, contraindications to nateglinide, pregnancy or possible pregnancy, and severe liver/renal failure. Patients who were considered to be unsuitable by the attending physician for other reasons were also excluded. Blood samples were collected at one and three hours after intake of a test meal. The primary outcome measure was the area under the curve (AUC) of apolipoprotein (Apo) B48 at three hours postprandially. RESULTS: Twenty patients were randomly assigned to the sitagliptin group and sixteen patients were randomized to the nateglinide group. All 36 patients took the medication as directed by the physician in both groups, and they all were analyzed. Apart from antidiabetic drugs, there was no difference between the two groups with respect to the frequency of combined use of lipid-lowering, antihypertensive, and/or antiplatelet drugs. The doses of these medications were maintained during 12 wk of treatment. Detailed dietary advice, together with adequate exercise therapy, was given to the patients so that other factors apart from the two test drugs were similar in the two groups. There were no significant differences of the baseline characteristics between the two groups, except for body mass index (the sitagliptin group: 25.14 ± 3.05 kg/m 2 ; the nateglinide group: 21.39 ± 2.24 kg/m 2 ). Fasting levels of HbA 1c , glycated albumin, 1.5-anhydroglucitol, and blood glucose, as well as the blood glucose levels at one and three hours postprandially, improved in both groups after 12 wk of treatment, and there were no significant differences between the two groups. However, the glucagon level at one hour postprandially (P = 0.040) and the diastolic blood pressure (P<0.01) only showed a significant decrease in the sitagliptin group. In the nateglinide group, there was no significant change in the AUC of Apo B48, the glucagon level at one hour postprandially, the fasting triglyceride level, or the diastolic blood pressure. Body weight was unchanged in both groups. However, the AUC of Apo B48 at three hours postprandially showed a significant decrease in the sitagliptin group from 2.48 ± 0.11 at baseline to 1.94 ± 0.78 g/L per hour after 12 wk (P=0.019). The fasting triglyceride level also decreased significantly in the sitagliptin group (P = 0.035). With regard to lipid-related markers other than Apo B48 and fasting triglycerides, no significant changes were observed with respect to Apo A1, Apo B, or Apo C3 in either group. No adverse events occurred in either group. CONCLUSION: Sitagliptin significantly improves some lipid parameters while having a comparable effect on blood glucose to nateglinide. A large-scale prospective study of sitagliptin therapy is warranted.展开更多
Diabetic neuropathies are a family of nerve disorders caused by diabetes. Symptoms of the disease include nerve palsy, mononeuropathy, mononeuropathy multiplex, diabetic amyotrophy, painful polyneuropathy, autonomic n...Diabetic neuropathies are a family of nerve disorders caused by diabetes. Symptoms of the disease include nerve palsy, mononeuropathy, mononeuropathy multiplex, diabetic amyotrophy, painful polyneuropathy, autonomic neu- ropathy, and thoracoabdominal neuropathy. In this study, type 2 diabetes in rats was induced with nicotinamide- streptozotocin. Drug treatment was initiated on the d 15, with the combination regimen of metformin, pioglitazone and glimipiride or metformin and sitagliptin or sitagliptin, amitriptyline and sitagliptin and led to significantly im- proved glycemic control, increased grip strength and paw jumping response on d 21, 28 and 35 （P 〈 0.001）. Signif- icant increases in blood protein levels and decreases in urinary protein levels were observed in the animals treated with the different regimens on d 21, 28 and 35 （P 〈 0.001）. Combined treatment of streptozotocin and nicotinamide caused marked degeneration of nerve cells, while administration of metformin and sitagliptin showed tissue regen- eration and no body weight gain. In conclusion, treatment with sitagliptin and sitagliptin combined with metformin or amitriptyline results in no body weight gain, but causes an increase in grip strength and pain sensitivity, exhibits neural protection, and reverses the alteration of biochemical parameters in rats with streptozotocin-nicotinamide induced type 2 diabetes.展开更多
AIM:To assess the effect of sitagliptin therapy on seasonal fluctuation of glycemic control in Japanese type 2 diabetic patients.METHODS:Participating patients(age:29-80 years) had been treated with conventional oral ...AIM:To assess the effect of sitagliptin therapy on seasonal fluctuation of glycemic control in Japanese type 2 diabetic patients.METHODS:Participating patients(age:29-80 years) had been treated with conventional oral antidiabetic agents and/or diet and exercise therapy for over 6 mo.From December 2009,35 patients were additionally prescribed oral sitagliptin starting from 50 mg once daily,while 19 patients taking-glucosidase inhibitors were switched to sitagliptin.Twenty-four patients who refused sitagliptin formed the control group.Changes of mean monthly hemoglobin A 1c(HbA 1c) during the "winter holiday season" were compared between groups using Student's t-test(2008-2009 vs 2009-2010).Statistical significance was accepted at P < 0.05.Multivariate analysis was performed to assess whether sitagliptin use was associated with deterioration or improvement of glycemic control.RESULTS:Both add-on sitagliptin and switching from-glucosidase inhibitors to sitagliptin prevented the seasonal deterioration of glycemic control and tended to improve HbA 1c.Multivariate analysis revealed that both adding and switching to sitagliptin were negatively correlated with deterioration of glycemic control.In 44 patients who continued sitagliptin therapy for another year,elevation of HbA 1c was suppressed without adverse effects.CONCLUSION:Sitagliptin is a suitable oral agent for preventing deterioration of glycemic control during the winter holiday season.展开更多
Sitagliptin is the first new anti-diabetic drug in DPP-Ⅳ inhibitor class. The general synthesis of sitagliptin is by coupling of the β-amino acid fragment with the heterocycle fragment. Though the specific β-amino ...Sitagliptin is the first new anti-diabetic drug in DPP-Ⅳ inhibitor class. The general synthesis of sitagliptin is by coupling of the β-amino acid fragment with the heterocycle fragment. Though the specific β-amino acid can be easily made from the corresponding R-amino acid by Arndt-Eistert hornologation, the optically pure precursor R-amino acid is difficult to prepare. We herein reported a practical protocol to make the trifluorophenyl substituted R-amino acid 4 in 〉99.9% ee and 40.3% yield by the enzymatic resolution employing enantioselective hydrolysis and a general separation procedure. This protocol requires only cheap starting materials and friendly reaction condition. The procedure not only allows people to prepare the drug substance, but also provides an alternative method for prepareing the rare α-amino acid and the subsequent β-amino acid.展开更多
To the Editor: A high prevalence of glucose intolerance in patients with chronic hepatitis C has been reported, [1] and there is a significant association of chronic hepatitis C with diabetes mellitus (DM). [2] But DM...To the Editor: A high prevalence of glucose intolerance in patients with chronic hepatitis C has been reported, [1] and there is a significant association of chronic hepatitis C with diabetes mellitus (DM). [2] But DM has been suggested to be associated with the onset of hepatocellular carcinoma展开更多
Describing a reported case of acute pancreatitis in a patient receiving sitagliptin. We present the biochemical and findings of a 60 year-old male who presented with severe abdominal pain and was found to have acute p...Describing a reported case of acute pancreatitis in a patient receiving sitagliptin. We present the biochemical and findings of a 60 year-old male who presented with severe abdominal pain and was found to have acute pancreatitis. This occurred one month after the commencement of sitagliptin, a dipeptidyl peptidase IV inhibitor, for the treatment of uncontrolled type 2 diabetes. Results: Pancreatic enzymes were elevated (i.e. amylase 204, lipase: 525.3) with a normal liver function test and a normal lipid profile. Ultrasound abdomen was unremarkable. In the absence of an identifiable cause for the patient’s pancreatitis, sitagliptin was considered a potential trigger and on ceasing this agent, the patient recovered from his condition. Conclusion: Incretin-based therapy is an effective line in the treatment of type 2 diabetes mellitus. FDA issued a warning letters to the drug company because of emerging reports of acute pancreatitis in patients receiving sitagliptin. This is unfortunately not the first reported case of acute pancreatitis in a patient receiving sitagliptin and it supports the possibility that acute pancreatitis may be the effect of incretin-based therapy.展开更多
A liquid chromatography tandem mass spectrometry (LC-MS/MS) based method was developed for the simultaneous monitoring plasma levels of Sitagliptin (STG) and Pioglitazone (PIO) for applicability to pharmacokinetic stu...A liquid chromatography tandem mass spectrometry (LC-MS/MS) based method was developed for the simultaneous monitoring plasma levels of Sitagliptin (STG) and Pioglitazone (PIO) for applicability to pharmacokinetic studies. The method was based on HPLC separation on the reversed phase Phenomenex Synergy C18 column (30 mm length, 4.6 mm internal diameter, and 4.0 μm particle size) at a temperature of 40?C using a binary gradient mobile phase consisting of methanol and 2 mM ammonium acetate buffer pH adjusted to 4.5 with acetic acid, at a flow rate of 1 mL?min?1. Tolbutamide was used as an internal standard. Detection of analytes was achieved with LC-MS/MS system in Multiple Reaction Monitoring (MRM) mode. The method was validated over concentration range of 10.98 - 2091.77 ng?mL?1 for SIT and 8.25 - 1571.63 ng?mL?1 for PIO and lower limit of quantification was 10.98 ng?mL?1 and 8.25 ng?mL?1 for STG and PIO respectively. Recoveries from spiked controls were within acceptance criteria for all the analytes and internal standard at all QC levels. Within batch and between batch accuracy for STG was found within 96.9% - 100.3% and for PIO was found within 100.0% - 104.3%. Within batch and between batch precision for STG was less than 3.1% CV (coefficient of variation) and for PIO was less than 5.3% CV at all concentrations levels. This method was successfully applied to monitor pharmacokinetics profile of both STG and PIO on simultaneous oral administration to rats. This method can be applicable for pharmacokinetic drug-drug interaction studies.展开更多
Triple-negative breast cancer(TNBC)cell line MDA-MB-231 is known for Warburg metabolism and defects in mitochondria.On the other hand,dipeptidyl peptidase-IV(DPP-IV)inhibitors such as sitagliptin and vildagliptin and ...Triple-negative breast cancer(TNBC)cell line MDA-MB-231 is known for Warburg metabolism and defects in mitochondria.On the other hand,dipeptidyl peptidase-IV(DPP-IV)inhibitors such as sitagliptin and vildagliptin and GLP-1 agonist exendin-4 are known to improve mitochondrial functions as well as biogenesis,but no study has evaluated the influence of these drugs on mitochondrial biogenesis on metastatic breast cancer cell line.We have recently reported anticancer effects of 5-aminoimidazole-4-carboxamide riboside on MDA-MB-231 cells via activation of AMP-dependent kinase(AMPK),which activates the downstream transcription factors PGC-1α,PGC-1β,or FOXO1 for mitochondrial biogenesis;above-mentioned incretin-based therapies are also known to activate AMPK.This study evaluated the effects of sitagliptin,vildagliptin,and exendin-4 on MDA-MB-231 cells and the underlying changes in mitochondrial biogenesis,were examined.Treatment with sitagliptin(100μM),vildagliptin(100μM),and exendin-4(10 nM)for 72 h to MDA-MB-231 cells led to a decrease in viability indicated by MTT assay,cell migration by scratch,and transwell migration assays,accompanied with marginal reduction in cell numbers along with the apoptotic appearance,the rate of apoptosis,and decreased lactate content in conditioned medium.These changes in the cancer phenotype were accompanied by an increase in the mitochondrial DNA to nuclear DNA ratio,increased MitoTracker green and red staining,and increased expression of transcription factors PGC-1α,NRF-1,NRF-2,TFAM,and HO-1.Pre-treatment of cells with these incretin-based drugs followed by 48 h treatment with 1μM doxorubicin increased doxorubicin sensitivity as observed by a decrease in viability by MTT assay.Thus,sitagliptin,vildagliptin,and exendin-4 exert their beneficial effects on TNBC cells via an increase in mitochondrial biogenesis that helps to switch Warburg metabolism into anti-Warburg effect.Therapeutic response was in the order of:sitagliptin>vildagliptin>exendin-4.展开更多
Objective Nonalcoholic fatty liver disease(NAFLD)is a common cause of clinical liver dysfunction and an important prepathological change of liver cirrhosis.Central obesity,type 2 diabetes mellitus,dyslipidemia,and met...Objective Nonalcoholic fatty liver disease(NAFLD)is a common cause of clinical liver dysfunction and an important prepathological change of liver cirrhosis.Central obesity,type 2 diabetes mellitus,dyslipidemia,and metabolic syndrome are the major risk factors for NAFLD.Sitagliptin(Sig)is a novel hypoglycemic agent that improves blood glucose levels by increasing the level of active incretin.Sig has been shown to prevent the development of fatty livers in mice on a fructose-rich diet.The purpose of this study was to observe the efficacy of Sig on NAFLD in type 2 diabetic mice.Methods The diet-induced obesity mouse model was established,and the diabetic mice were screened by an intraperitoneal glucose tolerance trial.The mice were randomly divided into four groups for 8 weeks of intervention:high-fat diet(HFD)group,Sig group,metformin(Met)group,and Sig+Met group.After the intervention,the liver function indexes as well as the blood glucose and blood lipid levels of the mice were measured.In addition,the wet weight of the liver was measured;the pathological sections of the liver tissues were stained to observe the hepatocyte fatty degeneration,inflammation,necrosis,and fibrosis;and the hepatic histological injury was recorded as the NAFLD activity score(NAS).Results Compared with the normal control group,the body weight,liver weight,blood glucose level,insulin resistance(IR),blood lipid level,and transaminase level of the mice in the HFD group were significantly increased,showing typical metabolic syndrome.After treatment with Sig and/or Met,the mice gained less weight,had lower levels of blood glucose,triglyceride(TG),low-density lipoprotein cholesterol(LDL-C),and transaminase,and had improved IR compared with the HFD group.The liver pathological NASs in the Sig group(P=0.01),Met group(P=0.028),and Sig+Met group(P<0.001)were lower than those in the HFD group(P<0.05),suggesting that the use of the two drugs alone or in combination can improve the state of liver inflammation.In terms of fibrosis,there was no fibrosis in the control group but there was significant fibrosis in the HFD group(P<0.001).There was no significant difference between the drug intervention groups and the HFD group,indicating that the drug therapy(Sig and/or Met)did not significantly improve the pre-existing fibrosis.Conclusion Our experiment proved that Sig can improve NAFLD,including improvement of the serum transaminase level,hepatic pathological inflammation level,and hepatocyte adiposis,suggesting that Sig may play a role by improving glucose and lipid metabolism,reducing the body weight and liver weight,improving insulin sensitivity,and inhibiting fatty liver inflammation.Sig may be a new direction for the treatment of patients with a nonalcoholic fatty liver and diabetes,delaying the progression of NAFLD.展开更多
We evaluated the effect of sitagliptin on vascular endothelial function in Japanese type 2 diabetes patients without cardiovascular disease. Subjects included 24 Japanese type 2 diabetes patients without cardiovascula...We evaluated the effect of sitagliptin on vascular endothelial function in Japanese type 2 diabetes patients without cardiovascular disease. Subjects included 24 Japanese type 2 diabetes patients without cardiovascular disease. This study was a prospective, open-label, randomized clinical trial. We divided the study subjects into 2 groups: subjects who received sitagliptin 50 mg daily (sitagliptin group, n = 12) and subjects who did not receive sitagliptin (control group, n = 12). Brachial artery flow-mediated dilation (FMD) was measured after overnight fasting. Sitagliptin administration was initiated at 1 month after enrollment in study (baseline). FMD and level of biochemical variables in the sitagliptin and control groups were measured at baseline and 3 months from baseline (3 months). We evaluated the effect of sitagliptin on vascular endothelial function by measuring FMD. FMD at 3 months was significantly higher in the sitagliptin group than in the control group (5.36% ± 2.18% vs 3.41% ± 2.29%, P = 0.040), while FMD at baseline was not significantly different between the 2 groups. In addition, FMD of the sitagliptin group at 3 months was significantly higher than that at baseline (5.36% ± 2.18% vs 3.67% ± 2.30%, P = 0.004), while no significant differences were observed in the FMD of the control group during the study period. The change in the adiponectin from baseline to 3 months was significantly higher in the sitagliptin group than that in the control group (0.82 ± 2.18 μg/mL vs 0.01 ± 0.55 μg/mL, P = 0.039). Sitagliptin improves vascular endothelial function of the brachial artery in Japanese type 2 diabetes patients without cardiovascular disease. Furthermore, elevation of adiponectin may induce reduction of endothelial dysfunction in type 2 diabetes patients treated with sitagliptin.展开更多
Japanese type 2 diabetic patients were treated with sitagliptin to evaluate the efficacy of this agent, and also to investigate the clinical characteristics of those who responded to sitagliptin. In total, 1001 diabet...Japanese type 2 diabetic patients were treated with sitagliptin to evaluate the efficacy of this agent, and also to investigate the clinical characteristics of those who responded to sitagliptin. In total, 1001 diabetic patients, inadequately controlled (HbA1c ≥ 6.5%) with oral hypoglycemic agents (OHA) other than DPP-4 inhibitors or with diet and exercise only, were enrolled. We added 50mg of sitagliptin to the therapeutic regimens of 410 patients including 68 OHA naive patients, while the other 591 patients were switched from a single OHA to 50 mg of sitagliptin. After 6 months, glycemic control was significantly improved due to both reduced insulin resistance, as demonstrated by a significant HOMA-R reduction, and recovery of pancreatic β cell function, as assessed by HOMA-β and the proinsulin/insulin (PI/I) ratio. In the bivariable analysis, a good response, defined as an HbA1c reduction during the 6 months of at least 0.9%, was associated with high HbA1c and PI/I at baseline and combination treatments with sulfonylurea, biguanide and α-glucosidase inhibitors, but not with obesity. On the other hand, in the multivariable regression analysis, only high baseline HbA1c and combination treatment with anα-glucosidase inhibitor were significantly associated with a good response to sitagliptin. In patients with type 2 diabetes, the addition of sitagliptin or switching from another OHA to this agent achieved an HbA1c reduction without overloading β cells. In particular, we suggest that a good response to sitagliptin can be expected when this agent is combined with an α-glucosidase inhibitor (UMIN No. #000014157).展开更多
Background: The purpose of this study was to evaluate the effects of sitagliptin in elderly patients with type 2 diabetes aged 75 years or older versus those aged 65 - 74 years. Methods: Outpatients aged 65 years or o...Background: The purpose of this study was to evaluate the effects of sitagliptin in elderly patients with type 2 diabetes aged 75 years or older versus those aged 65 - 74 years. Methods: Outpatients aged 65 years or older with type 2 diabetes who received sitagliptin at a dose of 50 mg daily for 6 months were divided into two groups: those who were 75 years and older and those who were 65 - 74 years. The efficacy and safety were retrospectively evaluated by comparison of laboratory values before and after the administration of sitagliptin and by review of adverse events after treatment. Results: One hundred and twelve older patients with type 2 diabetes were studied. Six months after the initiation of sitagliptin, participants’ hemoglobin A1c was significantly decreased by 1.09% ± 0.8% in 65 - 74-year-olds (66 patients;mean age, 69.1 ± 3.0 years;mean HbA1c before administration, 8.4% ± 0.8%) and by 1.05% ± 0.8% in patients 75 years or older (46 patients;mean age, 79.8 ± 4.1 years;mean HbA1c before administration, 8.5% ± 0.7%). There was no significant difference in hemoglobin A1c between the two groups. Furthermore, sitagliptin was well tolerated in both age groups. Conclusions: In elderly patients (75 years or older) with type 2 diabetes, the effect of sitagliptin was similar that in older patients (younger than 75 years) with type 2 diabetes.展开更多
Present study was aimed to develop and validate a reverse-phase high-performance liquid chromatography method for simultaneous determination of sitagliptin phosphate and metformin hy-drochloride in a marketed formulat...Present study was aimed to develop and validate a reverse-phase high-performance liquid chromatography method for simultaneous determination of sitagliptin phosphate and metformin hy-drochloride in a marketed formulation. The drug separation was performed on Hibar-240, Li-chrosphere-100 C18 ODS (250 × 4.6 mm, 5 μm) column, at a flow rate of 1 mL/min. The mobile phase used was a mixture of methanol: potassium di-hydrogen phosphate buffer at a ratio of 70:30 v/v. The detection was carried out at a wavelength of 266 nm. The retention times of sitagliptin phosphate and metformin hydrochloride were found as 6.1 and 4.9 min respectively. Linear calibration curves with good correlation coefficients were obtained over the concentration ranges of 10 - 50 μg/mL for sitagliptin and 20 - 100 μg/mL for metformin. The limit of detection was 0.016 and 0.14 μg/mL and the limit of quantification was 0.048 and 0.42 μg/mL for sitagliptin phosphate and metformin hydrochloride respectively. Validation of the method demonstrated system selectivity, specificity, linearity, accuracy and precision. The developed method was found useful in the simultaneous analysis of sitagliptin phosphate and metformin hydrochloride in formulation.展开更多
Objective:To study the effects of basal insulin combined with Sitagliptin Phosphate Tablets on blood glucose control, oxidative stress and inflammatory response.Methods: Type 2 diabetic patients with poor blood glucos...Objective:To study the effects of basal insulin combined with Sitagliptin Phosphate Tablets on blood glucose control, oxidative stress and inflammatory response.Methods: Type 2 diabetic patients with poor blood glucose control after metformin monotherapy in our hospital between March 2015 and July 2017 were selected as the research subjects and divided into two groups by random number table method. The experimental group received metformin + basal insulin + sitagliptin treatment, while control group were treated with metformin + glimepiride. The levels of glycosylated hemoglobin as well as the contents of oxidative stress indexes and inflammatory response indexes were measured before treatment and 3 months after treatment. Results: Compared with those before treatment, glycosylated hemoglobin levels, serum AGEs, MDA, CRP, TNF-α, IL-6, IL-8 and VCAM-1 contents as well as peripheral blood Nrf2, HO-1, NOX2 and NOX4 expression intensity of both groups were significantly decreased while serum SOD and CAT contents were significantly increased 3 months after treatment, and glycosylated hemoglobin level, serum AGEs, MDA, CRP, TNF-α, IL-6, IL-8 and VCAM-1 contents as well as peripheral blood Nrf2, HO-1, NOX2 and NOX4 expression intensity of experimental group 3 months after treatment were significantly lower than those of control group whereas serum SOD and CAT contents were significantly higher than those of control group (P<0.05).Conclusion: Basal insulin combined with Sitagliptin Phosphate Tablets can improve the blood glucose control condition and reduce the oxidative stress and inflammatory response in type 2 diabetic patients with poor blood glucose control after metformin monotherapy.展开更多
目的探讨达格列净治疗2型糖尿病(T2DM)合并高尿酸血症的疗效和安全性。方法122例2型糖尿病患者合并无症状高尿酸血症患者,随机分为对照组和观察组。对照组60例经过口服二甲双胍片1片tid联合磷酸西格列汀片1片QD治疗。观察组62例经过口...目的探讨达格列净治疗2型糖尿病(T2DM)合并高尿酸血症的疗效和安全性。方法122例2型糖尿病患者合并无症状高尿酸血症患者,随机分为对照组和观察组。对照组60例经过口服二甲双胍片1片tid联合磷酸西格列汀片1片QD治疗。观察组62例经过口服二甲双胍1片tid联合达格列净片1片QD治疗。两组患者均经过12周治疗。比较两组患者治疗前后的空腹血糖水平(FPG)、餐后2 h血糖水平(2 h PG)、糖化血红蛋白(HbAlc)、血尿酸(BUA)、血肌酐(Scr)、尿素氮(BUN)和不良反应发生情况。结果对照组1例失访。观察组2例未完成随访,其中1例因发生泌尿系感染,1例因胃肠道不耐受退出试验。治疗12周后观察组FPG、2 h PG、HbAlc、BUA和BUN均有显著性下降,而治疗后血糖达标率,Scr和不良反应两组无统计学差异。结论口服达格列净片治疗2型糖尿病合并无症状高尿酸血症能有效控制血糖,降低血尿酸水平,延缓相关并发症,具有一定的临床推广应用价值。展开更多
A new high-performance liquid chromatography （HPLC） method for the quantitative determination of sitagliptin in rat plasma was developed and validated for pharmacokinetics study. The plasma was spiked with the inter...A new high-performance liquid chromatography （HPLC） method for the quantitative determination of sitagliptin in rat plasma was developed and validated for pharmacokinetics study. The plasma was spiked with the internal standard （hydrocortisone, IS）, treated with sodium hydroxide, and extracted with ethyl acetate. The extracted analyte was injected into an Agilent Zorbax Extend-C18 column （250 mm×4.6 mm, 4 μm） maintained at 30℃ and monitored at 267 nm. The mobile phase consisting of methanol-water （60：40, v/v, containing 10 mM Tris and 10 mM triethylamine） was titrated to pH 9.0 using 1 mol/L hydrochloric acid. The flow rate was 1.0 mL/min. The method showed high specificity. Calibration curves of the peak area ratio of each analyte/IS versus sitagliptin concentration were linear in the range of 0.75-100.0μg/mL （r〉0.9957）. The lower limit of quantification （LLOQ） was 0.75 μg/mL. The intra-day and inter-day coefficient of variation was lower than 10%. The accuracy （relative recovery） at three levels was 105.3% （0.75 μg/mL）, 99.8% （10.0 μg/mL） and 99.0% （100.0 μg/mL）. The extraction recovery was 81.5%, 82.4% and 84.5% at the concentrations of 0.75, 10.0 and 100.0 μg/mL, respectively. The short-term, long-term, freeze-thaw storage stability of plasma samples and the stability of standard solutions were satisfactory. This HPLC method is suitable for determining the concentration of sitagliptin in rat plasma and it was applied to determine the concentration-time profiles of sitagliptin in rat plasma following oral administration of sitagliptin.展开更多
文摘BACKGROUND Early diabetic nephropathy(DN)is a complication of diabetes mellitus.It mainly affects kidney microvessels and glomerular function,and its timely and effective treatment is critical for early DN.However,the effects of treatments comprising simple Western medicine are not optimal.With the promotion and implementation of integrated Chinese and western medicine treatments,remarkable results have been achieved for many diseases.To this end,we explored the clinical efficacy of integrated traditional Chinese and western medicines for the treatment of early DN.AIM To investigate the effect of sitagliptin tablets combined with Yiqi yangyin huoxue decoction on clinical efficacy and hemorheology in patients with early DN.METHODS Through a retrospective analysis,123 patients with early DN were admitted to the endocrinology clinic of the Changzhou NO.7 People’s Hospital from January 2021 to October 2022 and were selected as study subjects.After rigorous screening,100 patients with early DN were enrolled.The control group(CG,n=50)and the observation group(OG,n=50)were divided according to the treatment method.The CG were treated with sitagliptin,and the OG were treated with sitagliptin plus the Yiqi yangyin huoxue decoction.Both groups were treated for 3 mo.For both groups,the baseline data and clinical efficacy were compared,and changes in blood glucose levels,lipid levels,renal function,and hematological indicators before(T0)and after(T1)treatment were assessed.RESULTS The total effective rate for the OG was 94.00%and that of the CG was 80.00%(P<0.05).After treatment(T1),the levels of fasting blood glucose,2 h postprandial glucose,total cholesterol,triacylglycerol,and low-density lipoprotein cholesterol in OG patients were obviously lower than those in the CG(P<0.05),and cystatin C,homocysteine,urinary microalbumin,and blood creatinine values in OG patients were also obviously lower than those in the CG(P<0.05);erythrocyte deposition,plasma viscosity,whole blood high shear viscosity,and whole blood low shear viscosity were markedly lower in OG patients than in the CG(P<0.05).CONCLUSION Sitagliptin combined with Yiqi yangyin huoxue decoction has a remarkable effect when used to treat patients with early DN.Further,it is helpful in improving hemorheological indices and controlling disease progression.
基金the Physicians’Services Incorporated Foundation 10q2083(Joy TR and Beaton MD)Academic Medical Organization of Southwestern Ontario,No.F10-002(Beaton MD)+1 种基金partly funded through academic research funds from the Program of Experimental Medicine(Joy TR)Department of Medicine Academic Funds(Joy TR)from Western University,London,Ontario,Canada
文摘AIMTo evaluate the effect of sitagliptin vs placebo on histologic and non-histologic parameters of non-alcoholic steatohepatitis (NASH).METHODSTwelve patients with biopsy-proven NASH were randomized to sitagliptin (100 mg daily) (n = 6) or placebo (n = 6) for 24 wk. The primary outcome was improvement in liver fibrosis after 24 wk. Secondary outcomes included evaluation of changes in NAFLD activity score (NAS), individual components of NAS (hepatocyte ballooning, lobular inflammation, and steatosis), glycemic control and insulin resistance [including measurements of glycated hemoglobin (HbA1C) and adipocytokines], lipid profile including free fatty acids, adipose distribution measured using magnetic resonance imaging (MRI), and thrombosis markers (platelet aggregation and plasminogen activator inhibitor 1 levels). We also sought to determine the correlation between changes in hepatic fat fraction (%) [as measured using the Iterative Decomposition of water and fat with Echo Asymmetry and Least-squares estimation (IDEAL) MRI technique] and changes in hepatic steatosis on liver biopsy.RESULTSSitagliptin was not significantly better than placebo at reducing liver fibrosis score as measured on liver biopsy (mean difference between sitagliptin and placebo arms, 0.40, P = 0.82). There were no significant improvements evident with the use of sitagliptin vs placebo for the secondary histologic outcomes of NAS total score as well as for the individual components of NAS. Compared to baseline, those patients who received sitagliptin demonstrated improved HbA1C (6.7% ± 0.4% vs 7.9% ± 1.0%, P = 0.02), and trended towards improved adiponectin levels (4.7 ± 3.5 μg/mL vs 3.9 ± 2.7 μg/mL, P = 0.06) and triglyceride levels (1.26 ± 0.43 mmol/L vs 2.80 ± 1.64 mmol/L, P = 0.08). However, when compared with placebo, sitagliptin did not cause a statistically significant improvement in HbA1C (mean difference, -0.7%, P = 0.19) nor triglyceride levels (mean difference -1.10 mmol/L, P = 0.19) but did trend towards improved adiponectin levels only (mean difference, 0.60 μg/mL, P = 0.095). No significant changes in anthropometrics, liver enzymes, other adipocytokines, lipid profile, thrombosis parameters, or adipose distribution were demonstrated. The MRI IDEAL procedure correlated well with steatosis scores obtained on liver biopsy in both groups at baseline and post-treatment, and the Spearman correlation coefficients ranged from r = 0.819 (baseline) to r = 0.878 (post-treatment), P = 0.002.CONCLUSIONSitagliptin does not improve fibrosis score or NAS after 24 wk of therapy. The MRI IDEAL technique may be useful for non-invasive measurement of hepatic steatosis.
基金supported by General Medical Science and Technology Plan Project of Zhejiang Province in 2016.(Grant No.:2016KYB214)
文摘Objective:To study the effect of sitagliptin on adipocytokines expression in diabetic rats and its molecular mechanism.Methods:Male SD rats were chosen and randomly divided into NC group,T2DM group,SP group and SP+LY group.NC group received conventional breeding,T2DM group,SP group and SP+LY group received intraperitoneal injection of streptozotocin after 12 weeks of high-fat diet to establish diabetes animal model,SP group received sitagliptin intervention and SP+LY group received sitagliptin combined with PI3 K inhibitor LY294002 intervention.6 weeks after the intervention,serum was collected to determine the levels of biochemical indexes and adipocytokines,and visceral adipose tissue was collected to determine expression levels of adipocytokines.Results:Serum TC,TG,LDL-C,FBG,FINS,Leptin and Chemerin levels as well as HOMA-IR of T2DM group were higher than those of NC group,and HDL-C,Adiponectin and Omentin-1 levels were significantly lower than those of NC group; serum TC,TG,LDL-C,FBG,FINS,Leptin and Chemerin levels as well as HOMA-IR of SP group were lower than those of T2DM group,and HDL-C,Adiponectin and Omentin-1 levels were significantly higher than those of T2DM group; Leptin and Chemerin levels in serum and visceral adipose tissue of SP+LY group were higher than those of SP group while Adiponectin and Omentin-1 levels were significantly lower than those of SP group.Conclusion:Sitagliptin can regulate the expression of adipocytokines in adipose tissue of diabetic rats through PI3K-AKT pathway.
文摘AIM: To assess the effects of sitagliptin and nateglinide on lipid metabolism. METHODS: In a parallel group comparative open trial, patients with type 2 diabetes mellitus under treatment at the Japanese Red Cross Medical Center were randomly assigned to receive either sitagliptin (50 mg once daily) or nateglinide (90 mg three times daily before meals). Eligible patients met the following criteria: age ≥ 20 years; hemoglobin A 1c (HbA 1c ) > 6.5% despite diet and exercise; HbA 1c between 6.5% and 8.0%; fasting glucose < 7.77 mmol/L; diet and exercise therapy for more than 3 mo; and ability to read and understand the information for written informed consent. Exclusion criteria were contraindications to sitagliptin, contraindications to nateglinide, pregnancy or possible pregnancy, and severe liver/renal failure. Patients who were considered to be unsuitable by the attending physician for other reasons were also excluded. Blood samples were collected at one and three hours after intake of a test meal. The primary outcome measure was the area under the curve (AUC) of apolipoprotein (Apo) B48 at three hours postprandially. RESULTS: Twenty patients were randomly assigned to the sitagliptin group and sixteen patients were randomized to the nateglinide group. All 36 patients took the medication as directed by the physician in both groups, and they all were analyzed. Apart from antidiabetic drugs, there was no difference between the two groups with respect to the frequency of combined use of lipid-lowering, antihypertensive, and/or antiplatelet drugs. The doses of these medications were maintained during 12 wk of treatment. Detailed dietary advice, together with adequate exercise therapy, was given to the patients so that other factors apart from the two test drugs were similar in the two groups. There were no significant differences of the baseline characteristics between the two groups, except for body mass index (the sitagliptin group: 25.14 ± 3.05 kg/m 2 ; the nateglinide group: 21.39 ± 2.24 kg/m 2 ). Fasting levels of HbA 1c , glycated albumin, 1.5-anhydroglucitol, and blood glucose, as well as the blood glucose levels at one and three hours postprandially, improved in both groups after 12 wk of treatment, and there were no significant differences between the two groups. However, the glucagon level at one hour postprandially (P = 0.040) and the diastolic blood pressure (P<0.01) only showed a significant decrease in the sitagliptin group. In the nateglinide group, there was no significant change in the AUC of Apo B48, the glucagon level at one hour postprandially, the fasting triglyceride level, or the diastolic blood pressure. Body weight was unchanged in both groups. However, the AUC of Apo B48 at three hours postprandially showed a significant decrease in the sitagliptin group from 2.48 ± 0.11 at baseline to 1.94 ± 0.78 g/L per hour after 12 wk (P=0.019). The fasting triglyceride level also decreased significantly in the sitagliptin group (P = 0.035). With regard to lipid-related markers other than Apo B48 and fasting triglycerides, no significant changes were observed with respect to Apo A1, Apo B, or Apo C3 in either group. No adverse events occurred in either group. CONCLUSION: Sitagliptin significantly improves some lipid parameters while having a comparable effect on blood glucose to nateglinide. A large-scale prospective study of sitagliptin therapy is warranted.
文摘Diabetic neuropathies are a family of nerve disorders caused by diabetes. Symptoms of the disease include nerve palsy, mononeuropathy, mononeuropathy multiplex, diabetic amyotrophy, painful polyneuropathy, autonomic neu- ropathy, and thoracoabdominal neuropathy. In this study, type 2 diabetes in rats was induced with nicotinamide- streptozotocin. Drug treatment was initiated on the d 15, with the combination regimen of metformin, pioglitazone and glimipiride or metformin and sitagliptin or sitagliptin, amitriptyline and sitagliptin and led to significantly im- proved glycemic control, increased grip strength and paw jumping response on d 21, 28 and 35 （P 〈 0.001）. Signif- icant increases in blood protein levels and decreases in urinary protein levels were observed in the animals treated with the different regimens on d 21, 28 and 35 （P 〈 0.001）. Combined treatment of streptozotocin and nicotinamide caused marked degeneration of nerve cells, while administration of metformin and sitagliptin showed tissue regen- eration and no body weight gain. In conclusion, treatment with sitagliptin and sitagliptin combined with metformin or amitriptyline results in no body weight gain, but causes an increase in grip strength and pain sensitivity, exhibits neural protection, and reverses the alteration of biochemical parameters in rats with streptozotocin-nicotinamide induced type 2 diabetes.
文摘AIM:To assess the effect of sitagliptin therapy on seasonal fluctuation of glycemic control in Japanese type 2 diabetic patients.METHODS:Participating patients(age:29-80 years) had been treated with conventional oral antidiabetic agents and/or diet and exercise therapy for over 6 mo.From December 2009,35 patients were additionally prescribed oral sitagliptin starting from 50 mg once daily,while 19 patients taking-glucosidase inhibitors were switched to sitagliptin.Twenty-four patients who refused sitagliptin formed the control group.Changes of mean monthly hemoglobin A 1c(HbA 1c) during the "winter holiday season" were compared between groups using Student's t-test(2008-2009 vs 2009-2010).Statistical significance was accepted at P < 0.05.Multivariate analysis was performed to assess whether sitagliptin use was associated with deterioration or improvement of glycemic control.RESULTS:Both add-on sitagliptin and switching from-glucosidase inhibitors to sitagliptin prevented the seasonal deterioration of glycemic control and tended to improve HbA 1c.Multivariate analysis revealed that both adding and switching to sitagliptin were negatively correlated with deterioration of glycemic control.In 44 patients who continued sitagliptin therapy for another year,elevation of HbA 1c was suppressed without adverse effects.CONCLUSION:Sitagliptin is a suitable oral agent for preventing deterioration of glycemic control during the winter holiday season.
基金supported in part by grant from Science and Technology Program of Guangdong Province(No. 2007B031503005).
文摘Sitagliptin is the first new anti-diabetic drug in DPP-Ⅳ inhibitor class. The general synthesis of sitagliptin is by coupling of the β-amino acid fragment with the heterocycle fragment. Though the specific β-amino acid can be easily made from the corresponding R-amino acid by Arndt-Eistert hornologation, the optically pure precursor R-amino acid is difficult to prepare. We herein reported a practical protocol to make the trifluorophenyl substituted R-amino acid 4 in 〉99.9% ee and 40.3% yield by the enzymatic resolution employing enantioselective hydrolysis and a general separation procedure. This protocol requires only cheap starting materials and friendly reaction condition. The procedure not only allows people to prepare the drug substance, but also provides an alternative method for prepareing the rare α-amino acid and the subsequent β-amino acid.
文摘To the Editor: A high prevalence of glucose intolerance in patients with chronic hepatitis C has been reported, [1] and there is a significant association of chronic hepatitis C with diabetes mellitus (DM). [2] But DM has been suggested to be associated with the onset of hepatocellular carcinoma
文摘Describing a reported case of acute pancreatitis in a patient receiving sitagliptin. We present the biochemical and findings of a 60 year-old male who presented with severe abdominal pain and was found to have acute pancreatitis. This occurred one month after the commencement of sitagliptin, a dipeptidyl peptidase IV inhibitor, for the treatment of uncontrolled type 2 diabetes. Results: Pancreatic enzymes were elevated (i.e. amylase 204, lipase: 525.3) with a normal liver function test and a normal lipid profile. Ultrasound abdomen was unremarkable. In the absence of an identifiable cause for the patient’s pancreatitis, sitagliptin was considered a potential trigger and on ceasing this agent, the patient recovered from his condition. Conclusion: Incretin-based therapy is an effective line in the treatment of type 2 diabetes mellitus. FDA issued a warning letters to the drug company because of emerging reports of acute pancreatitis in patients receiving sitagliptin. This is unfortunately not the first reported case of acute pancreatitis in a patient receiving sitagliptin and it supports the possibility that acute pancreatitis may be the effect of incretin-based therapy.
文摘A liquid chromatography tandem mass spectrometry (LC-MS/MS) based method was developed for the simultaneous monitoring plasma levels of Sitagliptin (STG) and Pioglitazone (PIO) for applicability to pharmacokinetic studies. The method was based on HPLC separation on the reversed phase Phenomenex Synergy C18 column (30 mm length, 4.6 mm internal diameter, and 4.0 μm particle size) at a temperature of 40?C using a binary gradient mobile phase consisting of methanol and 2 mM ammonium acetate buffer pH adjusted to 4.5 with acetic acid, at a flow rate of 1 mL?min?1. Tolbutamide was used as an internal standard. Detection of analytes was achieved with LC-MS/MS system in Multiple Reaction Monitoring (MRM) mode. The method was validated over concentration range of 10.98 - 2091.77 ng?mL?1 for SIT and 8.25 - 1571.63 ng?mL?1 for PIO and lower limit of quantification was 10.98 ng?mL?1 and 8.25 ng?mL?1 for STG and PIO respectively. Recoveries from spiked controls were within acceptance criteria for all the analytes and internal standard at all QC levels. Within batch and between batch accuracy for STG was found within 96.9% - 100.3% and for PIO was found within 100.0% - 104.3%. Within batch and between batch precision for STG was less than 3.1% CV (coefficient of variation) and for PIO was less than 5.3% CV at all concentrations levels. This method was successfully applied to monitor pharmacokinetics profile of both STG and PIO on simultaneous oral administration to rats. This method can be applicable for pharmacokinetic drug-drug interaction studies.
基金The work was supported by the Council of Scientific and Industrial Research-Junior Research Fellowship to Ms.Pooja Jaiswal(File No.09/301(0137)/2019-EMR-I)Ms.Versha Tripathi(09/301(0138)/2019-EMR-I)+1 种基金We also acknowledge the India-Belarus joint project(DST/INT/BLR/P-24/2019)funded by the Department of Science and TechnologyNew Delhi and the research grant from Devi Ahilya University,Indore(Dev/Seedmoney2.0/2020-21/655)sanctioned to Dr.Hamendra Singh Parmar.
文摘Triple-negative breast cancer(TNBC)cell line MDA-MB-231 is known for Warburg metabolism and defects in mitochondria.On the other hand,dipeptidyl peptidase-IV(DPP-IV)inhibitors such as sitagliptin and vildagliptin and GLP-1 agonist exendin-4 are known to improve mitochondrial functions as well as biogenesis,but no study has evaluated the influence of these drugs on mitochondrial biogenesis on metastatic breast cancer cell line.We have recently reported anticancer effects of 5-aminoimidazole-4-carboxamide riboside on MDA-MB-231 cells via activation of AMP-dependent kinase(AMPK),which activates the downstream transcription factors PGC-1α,PGC-1β,or FOXO1 for mitochondrial biogenesis;above-mentioned incretin-based therapies are also known to activate AMPK.This study evaluated the effects of sitagliptin,vildagliptin,and exendin-4 on MDA-MB-231 cells and the underlying changes in mitochondrial biogenesis,were examined.Treatment with sitagliptin(100μM),vildagliptin(100μM),and exendin-4(10 nM)for 72 h to MDA-MB-231 cells led to a decrease in viability indicated by MTT assay,cell migration by scratch,and transwell migration assays,accompanied with marginal reduction in cell numbers along with the apoptotic appearance,the rate of apoptosis,and decreased lactate content in conditioned medium.These changes in the cancer phenotype were accompanied by an increase in the mitochondrial DNA to nuclear DNA ratio,increased MitoTracker green and red staining,and increased expression of transcription factors PGC-1α,NRF-1,NRF-2,TFAM,and HO-1.Pre-treatment of cells with these incretin-based drugs followed by 48 h treatment with 1μM doxorubicin increased doxorubicin sensitivity as observed by a decrease in viability by MTT assay.Thus,sitagliptin,vildagliptin,and exendin-4 exert their beneficial effects on TNBC cells via an increase in mitochondrial biogenesis that helps to switch Warburg metabolism into anti-Warburg effect.Therapeutic response was in the order of:sitagliptin>vildagliptin>exendin-4.
基金Research Foundation of Beijing Friendship Hospital(No.yyqdkt2018-8).
文摘Objective Nonalcoholic fatty liver disease(NAFLD)is a common cause of clinical liver dysfunction and an important prepathological change of liver cirrhosis.Central obesity,type 2 diabetes mellitus,dyslipidemia,and metabolic syndrome are the major risk factors for NAFLD.Sitagliptin(Sig)is a novel hypoglycemic agent that improves blood glucose levels by increasing the level of active incretin.Sig has been shown to prevent the development of fatty livers in mice on a fructose-rich diet.The purpose of this study was to observe the efficacy of Sig on NAFLD in type 2 diabetic mice.Methods The diet-induced obesity mouse model was established,and the diabetic mice were screened by an intraperitoneal glucose tolerance trial.The mice were randomly divided into four groups for 8 weeks of intervention:high-fat diet(HFD)group,Sig group,metformin(Met)group,and Sig+Met group.After the intervention,the liver function indexes as well as the blood glucose and blood lipid levels of the mice were measured.In addition,the wet weight of the liver was measured;the pathological sections of the liver tissues were stained to observe the hepatocyte fatty degeneration,inflammation,necrosis,and fibrosis;and the hepatic histological injury was recorded as the NAFLD activity score(NAS).Results Compared with the normal control group,the body weight,liver weight,blood glucose level,insulin resistance(IR),blood lipid level,and transaminase level of the mice in the HFD group were significantly increased,showing typical metabolic syndrome.After treatment with Sig and/or Met,the mice gained less weight,had lower levels of blood glucose,triglyceride(TG),low-density lipoprotein cholesterol(LDL-C),and transaminase,and had improved IR compared with the HFD group.The liver pathological NASs in the Sig group(P=0.01),Met group(P=0.028),and Sig+Met group(P<0.001)were lower than those in the HFD group(P<0.05),suggesting that the use of the two drugs alone or in combination can improve the state of liver inflammation.In terms of fibrosis,there was no fibrosis in the control group but there was significant fibrosis in the HFD group(P<0.001).There was no significant difference between the drug intervention groups and the HFD group,indicating that the drug therapy(Sig and/or Met)did not significantly improve the pre-existing fibrosis.Conclusion Our experiment proved that Sig can improve NAFLD,including improvement of the serum transaminase level,hepatic pathological inflammation level,and hepatocyte adiposis,suggesting that Sig may play a role by improving glucose and lipid metabolism,reducing the body weight and liver weight,improving insulin sensitivity,and inhibiting fatty liver inflammation.Sig may be a new direction for the treatment of patients with a nonalcoholic fatty liver and diabetes,delaying the progression of NAFLD.
文摘We evaluated the effect of sitagliptin on vascular endothelial function in Japanese type 2 diabetes patients without cardiovascular disease. Subjects included 24 Japanese type 2 diabetes patients without cardiovascular disease. This study was a prospective, open-label, randomized clinical trial. We divided the study subjects into 2 groups: subjects who received sitagliptin 50 mg daily (sitagliptin group, n = 12) and subjects who did not receive sitagliptin (control group, n = 12). Brachial artery flow-mediated dilation (FMD) was measured after overnight fasting. Sitagliptin administration was initiated at 1 month after enrollment in study (baseline). FMD and level of biochemical variables in the sitagliptin and control groups were measured at baseline and 3 months from baseline (3 months). We evaluated the effect of sitagliptin on vascular endothelial function by measuring FMD. FMD at 3 months was significantly higher in the sitagliptin group than in the control group (5.36% ± 2.18% vs 3.41% ± 2.29%, P = 0.040), while FMD at baseline was not significantly different between the 2 groups. In addition, FMD of the sitagliptin group at 3 months was significantly higher than that at baseline (5.36% ± 2.18% vs 3.67% ± 2.30%, P = 0.004), while no significant differences were observed in the FMD of the control group during the study period. The change in the adiponectin from baseline to 3 months was significantly higher in the sitagliptin group than that in the control group (0.82 ± 2.18 μg/mL vs 0.01 ± 0.55 μg/mL, P = 0.039). Sitagliptin improves vascular endothelial function of the brachial artery in Japanese type 2 diabetes patients without cardiovascular disease. Furthermore, elevation of adiponectin may induce reduction of endothelial dysfunction in type 2 diabetes patients treated with sitagliptin.
文摘Japanese type 2 diabetic patients were treated with sitagliptin to evaluate the efficacy of this agent, and also to investigate the clinical characteristics of those who responded to sitagliptin. In total, 1001 diabetic patients, inadequately controlled (HbA1c ≥ 6.5%) with oral hypoglycemic agents (OHA) other than DPP-4 inhibitors or with diet and exercise only, were enrolled. We added 50mg of sitagliptin to the therapeutic regimens of 410 patients including 68 OHA naive patients, while the other 591 patients were switched from a single OHA to 50 mg of sitagliptin. After 6 months, glycemic control was significantly improved due to both reduced insulin resistance, as demonstrated by a significant HOMA-R reduction, and recovery of pancreatic β cell function, as assessed by HOMA-β and the proinsulin/insulin (PI/I) ratio. In the bivariable analysis, a good response, defined as an HbA1c reduction during the 6 months of at least 0.9%, was associated with high HbA1c and PI/I at baseline and combination treatments with sulfonylurea, biguanide and α-glucosidase inhibitors, but not with obesity. On the other hand, in the multivariable regression analysis, only high baseline HbA1c and combination treatment with anα-glucosidase inhibitor were significantly associated with a good response to sitagliptin. In patients with type 2 diabetes, the addition of sitagliptin or switching from another OHA to this agent achieved an HbA1c reduction without overloading β cells. In particular, we suggest that a good response to sitagliptin can be expected when this agent is combined with an α-glucosidase inhibitor (UMIN No. #000014157).
文摘Background: The purpose of this study was to evaluate the effects of sitagliptin in elderly patients with type 2 diabetes aged 75 years or older versus those aged 65 - 74 years. Methods: Outpatients aged 65 years or older with type 2 diabetes who received sitagliptin at a dose of 50 mg daily for 6 months were divided into two groups: those who were 75 years and older and those who were 65 - 74 years. The efficacy and safety were retrospectively evaluated by comparison of laboratory values before and after the administration of sitagliptin and by review of adverse events after treatment. Results: One hundred and twelve older patients with type 2 diabetes were studied. Six months after the initiation of sitagliptin, participants’ hemoglobin A1c was significantly decreased by 1.09% ± 0.8% in 65 - 74-year-olds (66 patients;mean age, 69.1 ± 3.0 years;mean HbA1c before administration, 8.4% ± 0.8%) and by 1.05% ± 0.8% in patients 75 years or older (46 patients;mean age, 79.8 ± 4.1 years;mean HbA1c before administration, 8.5% ± 0.7%). There was no significant difference in hemoglobin A1c between the two groups. Furthermore, sitagliptin was well tolerated in both age groups. Conclusions: In elderly patients (75 years or older) with type 2 diabetes, the effect of sitagliptin was similar that in older patients (younger than 75 years) with type 2 diabetes.
文摘Present study was aimed to develop and validate a reverse-phase high-performance liquid chromatography method for simultaneous determination of sitagliptin phosphate and metformin hy-drochloride in a marketed formulation. The drug separation was performed on Hibar-240, Li-chrosphere-100 C18 ODS (250 × 4.6 mm, 5 μm) column, at a flow rate of 1 mL/min. The mobile phase used was a mixture of methanol: potassium di-hydrogen phosphate buffer at a ratio of 70:30 v/v. The detection was carried out at a wavelength of 266 nm. The retention times of sitagliptin phosphate and metformin hydrochloride were found as 6.1 and 4.9 min respectively. Linear calibration curves with good correlation coefficients were obtained over the concentration ranges of 10 - 50 μg/mL for sitagliptin and 20 - 100 μg/mL for metformin. The limit of detection was 0.016 and 0.14 μg/mL and the limit of quantification was 0.048 and 0.42 μg/mL for sitagliptin phosphate and metformin hydrochloride respectively. Validation of the method demonstrated system selectivity, specificity, linearity, accuracy and precision. The developed method was found useful in the simultaneous analysis of sitagliptin phosphate and metformin hydrochloride in formulation.
文摘Objective:To study the effects of basal insulin combined with Sitagliptin Phosphate Tablets on blood glucose control, oxidative stress and inflammatory response.Methods: Type 2 diabetic patients with poor blood glucose control after metformin monotherapy in our hospital between March 2015 and July 2017 were selected as the research subjects and divided into two groups by random number table method. The experimental group received metformin + basal insulin + sitagliptin treatment, while control group were treated with metformin + glimepiride. The levels of glycosylated hemoglobin as well as the contents of oxidative stress indexes and inflammatory response indexes were measured before treatment and 3 months after treatment. Results: Compared with those before treatment, glycosylated hemoglobin levels, serum AGEs, MDA, CRP, TNF-α, IL-6, IL-8 and VCAM-1 contents as well as peripheral blood Nrf2, HO-1, NOX2 and NOX4 expression intensity of both groups were significantly decreased while serum SOD and CAT contents were significantly increased 3 months after treatment, and glycosylated hemoglobin level, serum AGEs, MDA, CRP, TNF-α, IL-6, IL-8 and VCAM-1 contents as well as peripheral blood Nrf2, HO-1, NOX2 and NOX4 expression intensity of experimental group 3 months after treatment were significantly lower than those of control group whereas serum SOD and CAT contents were significantly higher than those of control group (P<0.05).Conclusion: Basal insulin combined with Sitagliptin Phosphate Tablets can improve the blood glucose control condition and reduce the oxidative stress and inflammatory response in type 2 diabetic patients with poor blood glucose control after metformin monotherapy.
文摘目的探讨达格列净治疗2型糖尿病(T2DM)合并高尿酸血症的疗效和安全性。方法122例2型糖尿病患者合并无症状高尿酸血症患者,随机分为对照组和观察组。对照组60例经过口服二甲双胍片1片tid联合磷酸西格列汀片1片QD治疗。观察组62例经过口服二甲双胍1片tid联合达格列净片1片QD治疗。两组患者均经过12周治疗。比较两组患者治疗前后的空腹血糖水平(FPG)、餐后2 h血糖水平(2 h PG)、糖化血红蛋白(HbAlc)、血尿酸(BUA)、血肌酐(Scr)、尿素氮(BUN)和不良反应发生情况。结果对照组1例失访。观察组2例未完成随访,其中1例因发生泌尿系感染,1例因胃肠道不耐受退出试验。治疗12周后观察组FPG、2 h PG、HbAlc、BUA和BUN均有显著性下降,而治疗后血糖达标率,Scr和不良反应两组无统计学差异。结论口服达格列净片治疗2型糖尿病合并无症状高尿酸血症能有效控制血糖,降低血尿酸水平,延缓相关并发症,具有一定的临床推广应用价值。
基金National Integrity Innovational Technology Platform of New Drug and Research and Development (Grant No. 2009ZX09301-010)National Fund for Talent Training in Basic Science
文摘A new high-performance liquid chromatography （HPLC） method for the quantitative determination of sitagliptin in rat plasma was developed and validated for pharmacokinetics study. The plasma was spiked with the internal standard （hydrocortisone, IS）, treated with sodium hydroxide, and extracted with ethyl acetate. The extracted analyte was injected into an Agilent Zorbax Extend-C18 column （250 mm×4.6 mm, 4 μm） maintained at 30℃ and monitored at 267 nm. The mobile phase consisting of methanol-water （60：40, v/v, containing 10 mM Tris and 10 mM triethylamine） was titrated to pH 9.0 using 1 mol/L hydrochloric acid. The flow rate was 1.0 mL/min. The method showed high specificity. Calibration curves of the peak area ratio of each analyte/IS versus sitagliptin concentration were linear in the range of 0.75-100.0μg/mL （r〉0.9957）. The lower limit of quantification （LLOQ） was 0.75 μg/mL. The intra-day and inter-day coefficient of variation was lower than 10%. The accuracy （relative recovery） at three levels was 105.3% （0.75 μg/mL）, 99.8% （10.0 μg/mL） and 99.0% （100.0 μg/mL）. The extraction recovery was 81.5%, 82.4% and 84.5% at the concentrations of 0.75, 10.0 and 100.0 μg/mL, respectively. The short-term, long-term, freeze-thaw storage stability of plasma samples and the stability of standard solutions were satisfactory. This HPLC method is suitable for determining the concentration of sitagliptin in rat plasma and it was applied to determine the concentration-time profiles of sitagliptin in rat plasma following oral administration of sitagliptin.
