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Objective:To investigate clinical characteristics of bullous pemphigoid (BP) developing after the treatment with dipeptidyl peptidase-Ⅳ inhibitors (DPP4i) in patients with diabetes mellitus.Methods:A total of 116 inpatients with BP complicated by diabetes mellitus were collected from the Seventh People′s Hospital of Shenyang between January 2014 and December 2020, and divided into 2 groups: DPP4i-BP group treated with DPP4i before the onset of BP, and general BP group receiving no treatment with DPP4i. General clinical data, skin lesion area, laboratory indicators, treatment regimens, and prognosis were analyzed and compared between the above 2 groups, the time interval from the administration of DPP4i to the diagnosis of BP was recorded in the DPP4i-BP group. One-way analysis of variance was used to compare measurement data among multiple groups, two-independent-sample t test was used for comparisons between two groups, and paired t-test for intra-group comparisons before and after treatment; chi-square test was used to compare enumeration data between groups. Results:There were 32 patients aged 77.17 ± 15.32 years in the DPP4i-BP group, with a male-to-female ratio being 15∶17; there were 84 patients aged 76.65 ± 19.32 years in the general BP group, with a male-to-female ratio being 43∶41. The time interval from the administration of DPP4i to the diagnosis of BP was 14.61 ± 3.93 months in the DPP4i-BP group. The time interval for vildagliptin was the shortest (5.42 ± 2.84 months) , and there was a significant difference in the time interval among vildagliptin, sitagliptin, linagliptin and saxagliptin ( F= 8.93, P < 0.001) . The proportion of patients with severe BP was significantly higher in the DPP4i-BP group (16 cases, 50%) than in the general BP group (25 cases, 29.76%; Z= 2.63, P= 0.008) . There was no significant difference in the positivity rate of anti-BP180 antibody between the two groups ( χ2= 0.03, P= 0.870) . However, the level of anti-BP180 antibody was significantly higher in the DPP4i-BP group than in the general BP group before and after treatment ( P= 0.015, < 0.001, respectively) , and the decrease in the level of anti-BP180 antibody was significantly less in the DPP4i-BP group than in the general BP group after treatment ( t= 5.11, P < 0.001) . There was no significant difference in the average effective dose of glucocorticoids required to control the disease between the two groups ( t= 1.00, P= 0.322) . However, the DPP4i-BP group showed a significant increase in the average time required to control the disease and in the proportion of patients requiring combined treatment with immunosuppressants or other drugs compared with the general BP group ( t= 6.72, 10.05, P < 0.001,= 0.002, respectively) . Within 6 months after the start of systemic treatment, the recurrence rate was significantly higher in the general BP group (17 cases, 27.86%) than in the DPP4i-BP group (2 cases, 7.69%; χ2= 4.35, P= 0.037) ; at 6 months, the average dose of glucocorticoids was also significantly higher in the general BP group than in the DPP4i-BP group ( t= 7.04, P < 0.001) . Conclusions:Among the DPP4i hypoglycemic drugs, vildagliptin was the most common drug administrated by patients before the onset of BP, with the shortest interval from the administration to the onset of BP. DPP4i-BP may be difficult to control at the early stage, but the prognosis is good.
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The clinical data of 96 patients with type 2 diabetes mellitus (T2DM) treated in Department of endocrinology of our hospital from January 2016 to December 2017 were retrospectively analyzed. All patients had been treated with metformin ≥1 000 mg combined with sulfonylureas for>12 weeks and their glycosylated hemoglobin (HbA1c) was>7.5%. On the basis of the original scheme, 57 patients received oral sitagliptin (100 mg q.d, sitagliptin group) and 39 patients received insulin glargine injection (insulin group) for 26 weeks. The blood lipid, liver and kidney function were examined before and after treatment. The abdominal visceral fat area (VFA) was measured by CT scan. Results showed that the fasting plasma glucose (FPG) , 2-hour postprandial blood glucose (2 hPG) and HbA1c were significantly lower than baseline levels in both groups(P<0.05). The decrease of VFA in sitagliptin and insulin groups was by 9.6 (1.4,19.6)cm2 and by 8.3(-2.2,26.8) cm2, respectively; there was significant difference in variation of VFA before and after treatment between the two groups (P<0.05). There was no significant difference in blood pressure, liver function (ALT, AST) and estimated glomerular filtration rate (eGFR) before and after treatment in the sitagliptin group (P>0.05). Additional sitagliptin administration can effectively and safely reduce HbA1c and decrease the abdominal visceral fat content in T2DM patients who failed to metformin and sulfonylureas combined therapy.
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Objective To investigate the effect of alogliptin on albuminuria in patients with early type 2 diabetic kidney disease (DKD) and the related mechanism.Methods One hundred patients with early DKD admitted in our hospital from May 2016 to May 2017 were randomly divided into two groups with 50 cases in each group.Patients in the control group were given metformin and gliclazide,while those in study group were given metformin and alogliptin,the treatment lasted for 24 weeks.The changes of urinary albumin-to-creatinine ratio (UACR),stromal cell-derived factor-1α (SDF-1α) and the fasting plasma glucose (FPG),2-h postprandial plasma glucose (2 hPPG),glycosylated hemoglobin(HbA1c) were measured before and after the treatment in two groups.Results There were no significant differences in HbA1c [(8.17± 0.46)％ vs.(8.29±0.48)％],UACR[(109±53) vs.(105±48)mg/g],SDF-1α [(1.21±0.3 9) vs.(1.17±0.35)μg/L] levels before treatment between two groups (t=0.343,0.464,0.075,all P＞0.05).After treatment,the HbA1c levels were significantly decreased in both groups (t=2.293,2.302,all P=0.03) and there was no significant difference between two groups[(6.82±0.75)％ vs.(6.93 ±0.79)％,t=0.295,P=0.77];the UACR levels were significantly reduced in both groups,but the level of study group was significantly lower than that of control group [(82±38) vs.(94±47) mg/g,t=3.320,P＜0.01];the SDF-1α levels were significantly increased in both groups,but the level of study group was significantly higher than that of control group[(3.01 ±0.38) vs.(2.76±0.42)μg/L,t=5.474,P＜0.01].There was no significant difference in the incidence of adverse reactions between the two groups [13％ (6/46) vs.12％ (6/48),x2=0.002,P＞0.05].Conclusion Alogliptin can effectively control the blood glucose,reduce urine albumin excretion and protect renal function in patients with early type 2 diabetic nephropathy,which is associated with the increased SDF-1α levels.
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Objective To investigate sitagliptin and repaglinide could ameliorate endothelial function in newly diagnosed type 2 diabetes patients and to explore its mechanism.Methods A total of 92 newly diagnosed type 2 diabetes patients with glycated hemoglobin A1c (HbA1c) from 6.5％ to 8.5％ was randomly assigned to sitagliptin group(n =46) receiving sitagliptin,and repaglinide group (n =46) receiving repaglinide for 12 weeks.The effect of sitagliptin on vascular endothelial function was measured with endothelium-dependent flow-mediated vasodilation (FMD).FMD,level of serum nitric oxide (NO),plasminogen activator inhibitor-1 (PAI-1) and biochemical variables in the two groups were measured at baseline and 12 weeks after treatment.Results Fasting blood glucose (FBG),postprandial blood glucose (PBG),and HbA1c decreased significantly both in sitagliptin and repaglinide groups after treatment,but the descent more significantly in the repaglinide group than those in the sitagliptin group (P ＜ 0.05).FMD,NO,and homeostasis model assessmentβ (HOMA-[β) were increased,and PAI-1 and homeostasis model assessment-insulin resistance (HOMR-IR) decreased in both two groups of patients (P ＜ 0.05).FMD,NO,and PAI-1 improved more significantly in sitagliptin groups (P ＜ 0.05).With FMD as dependent variables,multiple linear regression analysis showed that NO was a major protection factors of endothelial function,and PAI-1 and mean artery pressure (MAP) were major injury factors of endothelial function.Furthermore,with /FMD as the dependent variable,FMD as the dependent variable,and body mass index (BMI),MAP,HbA1c,HOMA-IR,triglycerides (TG),NO,and PAI-1 as a covariate-linear analysis of covariance showed that improved FMD with NO and PAI-1 were still relevant after treatment with sitagliptin.Conclusions Sitagliptin could improve vascular endothelial function evaluated by FMD better than repaglinide in newly diagnosed type 2 diabetes,the partial mechanism was related to the increase of NO level and the decrease of PAI-1 level,and the effect may be independent of the hypoglycemic effect.
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Objective To investigate sitagliptin and repaglinide could ameliorate endothelial function in newly diagnosed type 2 diabetes patients and to explore its mechanism.Methods A total of 92 newly diagnosed type 2 diabetes patients with glycated hemoglobin A1c (HbA1c) from 6.5％ to 8.5％ was randomly assigned to sitagliptin group(n =46) receiving sitagliptin,and repaglinide group (n =46) receiving repaglinide for 12 weeks.The effect of sitagliptin on vascular endothelial function was measured with endothelium-dependent flow-mediated vasodilation (FMD).FMD,level of serum nitric oxide (NO),plasminogen activator inhibitor-1 (PAI-1) and biochemical variables in the two groups were measured at baseline and 12 weeks after treatment.Results Fasting blood glucose (FBG),postprandial blood glucose (PBG),and HbA1c decreased significantly both in sitagliptin and repaglinide groups after treatment,but the descent more significantly in the repaglinide group than those in the sitagliptin group (P ＜ 0.05).FMD,NO,and homeostasis model assessmentβ (HOMA-[β) were increased,and PAI-1 and homeostasis model assessment-insulin resistance (HOMR-IR) decreased in both two groups of patients (P ＜ 0.05).FMD,NO,and PAI-1 improved more significantly in sitagliptin groups (P ＜ 0.05).With FMD as dependent variables,multiple linear regression analysis showed that NO was a major protection factors of endothelial function,and PAI-1 and mean artery pressure (MAP) were major injury factors of endothelial function.Furthermore,with /FMD as the dependent variable,FMD as the dependent variable,and body mass index (BMI),MAP,HbA1c,HOMA-IR,triglycerides (TG),NO,and PAI-1 as a covariate-linear analysis of covariance showed that improved FMD with NO and PAI-1 were still relevant after treatment with sitagliptin.Conclusions Sitagliptin could improve vascular endothelial function evaluated by FMD better than repaglinide in newly diagnosed type 2 diabetes,the partial mechanism was related to the increase of NO level and the decrease of PAI-1 level,and the effect may be independent of the hypoglycemic effect.
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Objective To explore the protective effects of dipeptidyl peptidase-4 inhibitor (DPP-4I) on AD-like neurodegenerative changes and its mechanism. Methods The human neuroblastoma cell line SH-SY5Y on the logarithmic phase was divided into six groups:control group (CON group, treated with PBS contained 1‰DMSO for 12 h), wortmannin intervention group (W group, treated with 0.03 μmol/L wortmannin for 12 h), DPP-4I intervention group (DPP-4I group, treated with 10μmol/L DPP-4I for 12 h), both DPP-4I and wortmannin intervention group (DPP-4I+W group, pre-treated with 10 μmol/L DPP-4I for 2 h, then 0.03 μmol/L wortmannin for 12 h), DPP-4I, wortmannin and Ex9-39 intervention group (DPP-4I+W+Ex9-39 group, pre-treated with 10μmol/L Ex9-39 for 2 h, then 10μmol/L DPP-4I for 2 h followed by 0.03μmol/L wortmannin for 12 h), and Ex9-39 intervention group (Ex9-39 group, treated with 10μmol/L Ex9-39 for 12 h). MTT assay was used to detect the cell vitality. Western blot assay was used to detect the level of total tau protein (tau-5) and phosphorylated tau at different sites (pSpS199/202, pT231 and pS396), the level of phosphorylated neurofilaments (NF-H, NF-M) and phosphorylation of critical enzyme in PI3K/Akt/GSK-3β signaling pathway. Results (1) The cell vitality decreased, the levels of pSpS199/202, pT231, pS396 and NF-H/M increased significantly in W group than those in CON group. However, comparing with CON group, the above mentioned parameters reversed in DPP-4I group. Comparing with W group, the cell vitality increased and phosphorylated levels of above mentioned indices were decreased in DPP-4I+W group. (2) The cell vitality showed a decline trend while the levels of phosphorylation tau at three different sites and NF-H/M were higher in Ex9-39 group than those in CON group. Comparing with DPP-4I+W group, the results of the phosphorylated levels showed the same changes in DPP-4I+W+Ex9-39 group. (3) Comparing with CON group, the expression levels of phosphorylated PI3K, Akt and GSK3β increased significantly in DPP-4I group, while those decreased in W group. Additionally, the expression levels of phosphorylated PI3K, Akt and GSK3β were significantly increased in DPP-4I+W group than those in W group. Conclusion DPP-4I can enhance the level of GLP-1 and activate PI3K/Akt/GSK-3βinsulin signaling pathway to improve the hyperphosphorylated tau and NFs induced by wortmannin, and to protect AD-like neurodegeneration.
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Vildagliptin is a kind of dipeptidyl peptidase Ⅳ(DPP-4) inhibitors. It is a new oral diabetes drug which is developed by Novartis. It reduces blood glucose levels by decreasing the concentration of glucagon,has remarkable advantages in drug safety and is widely used in the treatment of type 2 diabetes in clinic. In this paper,we summarize the synthetic methods of vildagliptin that have been reported in literature in recent years and their advantages and disadvantages.
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Objective To investigate the mechanism of a dipeptidyl-peptidase-4 (DPP-4) inhibitor, saxagliptin, pro?moting the regeneration of islet beta cells in diabetic rats. Methods The male SD rats were randomly divided into three groups including control group (NC, n=10), diabetes group (DM, n=10) and diabetes treated with saxagliptin group (DM-S, n=10). DM-S group was treated with saxagliptin 1 mg/(kg·d) for twelve weeks. The pancreaticβcell function was analysed by hyperglycemic clamps. Immunohistochemistry with anti-PCNA was performed to observe the proliferation rate of pancreaticβcells. Immunofluorescence double staining with anti-insulin, anti-glucagon, anti-DPP-4 and anti-SDF-1 were performed to observe the expression of insulin, glucagon, DPP-4 and SDF-1 in pancreatic tissue. Western blot assay was performed to test the expression of Akt, p-Akt,β-catenin and free-β-catenin protein, and RT-PCR was performed to test the expressionlevels of c-myc and cyclinD1 mRNA in pancreatic tissue. Results Compared with NC group, there were significantly in?creased blood glucose, decreased islet function andβcell mass in DM group. Compared with DM rats, saxagliptin treatment significantly inhibited the expression of DPP-4, decreased the degradation of SDF-1, stimulated the proliferation ofβcells, and ultimately improved the islet function and histopathological changes of pancreas. Conclusion DPP-4 inhibitor saxa?gliptin can significantly improve islet function, which involved in the inhibition of the expression of DPP-4, the decreased degradation of SDF-1 and the stimulation of the proliferation ofβcells.
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Pharmacoeconomic researches have confirmed that hypoglycemic treatment strategies including a dipeptidyl peptidase-Ⅳ (DPP-4) inhibitor exhibit excellent cost-effectiveness when compared with others.Direct comparisons with active glucose-lowering comparators in drug-naive patients have demonstrated that DPP-4 inhibitors exert slightly less pronounced HbA1c reduction than metformin (with the advantage of better gastrointestinal tolerability) and similar glucose-lowering effects compared with a thiazolidinedione (TZD,with the advantage of no weight gain).In metformin-treated patients,gliptins were associated with similar HbA1C reductions compared with a sulphonylurea(SU,with the advantage of no weight gain,considerably fewer hypoglycaemic episodes and no need for titration) and a TZD (with the advantage of no weight gain and better overall tolerability).In addition,excellent efficacy could also reduce the incidence of diabetic complications and increase patient's work productivity and thus lower indirect cost.