RESUMO
PURPOSE: This study comprises an investigation of the role of meteorin-like (Metrnl) in an experimental model of diabetic kidney disease (DKD). METHODS: Twenty-four db/db mice were randomly assigned to one of the following groups: DKD, DKD + Metrnl-/-, and DKD + Metrnl+/+. Plasma Metrnl concentrations were measured using ELISA. Kidney tissues were examined via western blotting, qRT-PCR, and immunohistochemistry to determine the expression levels of inflammatory factors. Electron microscopy was employed to observe stained kidney sections. RESULTS: Compared with the NC group, FBG, BW, and UACR were elevated in the DKD and Metrnl-/- groups, with severe renal pathological injury, decreased serum Metrnl concentration, decreased renal Metrnl expression, and increased expression levels of TNF-α, TGF-ß1, TGF-R1, pSmad2, pSmad3, and α-SMA. In contrast, the Metrnl+/+ group showed decreased FBG and UACR, BUN, TC and TG, increased HDL-C and serum Metrnl concentration, increased renal Metrnl expression, and decreased expression of TNF-α, TGF-ß1, TGF-R1, pSmad2, pSmad3, and α-SMA, compared to the DKD and Metrnl-/- groups. A Pearson bivariate correlation analysis revealed a negative correlation between UACR and Metrnl, and a positive correlation between UACR and TGF-ß1. CONCLUSION: Upregulation of renal Metrnl expression can improve renal injury by downregulating the expression of molecules in the TGF-ß1/Smads signaling pathway in the renal tissues of type 2 diabetic mice; and by reducing the production of fibrotic molecules such as α-SMA.
Assuntos
Nefropatias Diabéticas , Transdução de Sinais , Fator de Crescimento Transformador beta1 , Regulação para Cima , Animais , Nefropatias Diabéticas/metabolismo , Nefropatias Diabéticas/patologia , Nefropatias Diabéticas/genética , Fator de Crescimento Transformador beta1/metabolismo , Fator de Crescimento Transformador beta1/genética , Camundongos , Rim/metabolismo , Rim/patologia , Masculino , Camundongos Endogâmicos C57BL , Proteínas Smad/metabolismo , Camundongos Knockout , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Experimental/genéticaRESUMO
Studies have shown that the DPP-4 inhibitor was effective in improving skin damage in patients with psoriasis, but the exact mechanism was not known. To investigate the therapeutic effects of linagliptin in mice with type 2 diabetes mellitus (T2DM) with psoriasis and its possible therapeutic mechanisms. A total of 32 db/db mice and 16 db/m mice were randomly divided into six groups: normal group, psoriasis group, diabetes group, diabetes combined with psoriasis group, linagliptin-treated diabetes group, and linagliptin-treated diabetes combined with psoriasis group. The levels of serum fasting blood glucose, total cholesterol (TC), triglyceride (TG), high-density lipoprotein cholesterol, and low-density lipoprotein cholesterol were measured; the levels of serum FINS were determined by enzyme-linked immunoassay and the insulin resistance index was calculated. Basic parameters of diabetes, Psoriasis Area and Severity Index, histopathology of skin, the expression of interleukin (IL)-17A, IL-23, IL-22, and tumor necrosis factor (TNF)-α, and expression levels of measuring p-ERK, p-MAPK and p-nuclear factor kappa B (NF-κB) in skin tissues were measured. After treatment with linagliptin, insulin resistance, and TC and TG levels were reduced in mice with T2DM and psoriasis (p < .05). Moreover, the degree of epidermal tissue thickening, number of keratinized layers, and inflammatory cell infiltration were also reduced (p < .05), as well as the expression levels of inflammatory factors: TNF-α, IL-1ß, IL-17A, IL-23, and p-P38/P38, p-ERK/ERK, p-P65/P65 proteins (p < .05). Linagliptin significantly reduced the extent of skin lesions and skin inflammation. The underlying mechanism of this compound may be related to the inhibition of MAPK/NF-κB inflammatory pathways and the consequential improvement of insulin resistance.Significance Statement: In this study, we evaluated the therapeutic effect of the DPP-4 inhibitor linagliptin using a murine model of type 2 diabetes combined with psoriasis, and its potential mechanisms of action were further explored. The results of this study will help to uncover the pathogenesis of type 2 diabetes and psoriasis and, more importantly, provide a theoretical basis for the search for safe and effective drugs in the treatment of this specific patient population.
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Diabetes Mellitus Experimental , Diabetes Mellitus Tipo 2 , Linagliptina , Psoríase , Animais , Colesterol , Diabetes Mellitus Experimental/tratamento farmacológico , Diabetes Mellitus Tipo 2/tratamento farmacológico , Inibidores da Dipeptidil Peptidase IV , Hipoglicemiantes/uso terapêutico , Imiquimode/efeitos adversos , Resistência à Insulina , Interleucina-23 , Linagliptina/uso terapêutico , Camundongos , NF-kappa B/metabolismo , Psoríase/induzido quimicamente , Psoríase/tratamento farmacológico , Psoríase/patologia , Fator de Necrose Tumoral alfaRESUMO
OBJECTIVE: There were some clinical studies on GLP-1R agonist liraglutide therapy for psoriasis patients with type 2 diabetes, but there is a lack of randomized controlled trials and the mechanism of which remains unclear. METHOD: A total of 25 psoriasis patients with type 2 diabetes were randomized 1: 1 divided into the control group (n = 13) or liraglutide group (n = 12) for 12 weeks. We determined the PASI, the DLQI, histopathology of psoriasis skin, and the expression of IL-17, IL-23, and TNF-α in the psoriasis skin. RESULTS: After 12 weeks of treatment, the mean DLQI of the treatment group decreased from 22.00 ± 5.85 to 3.82 ± 3.60 (p < .05). Compared to week 12, the change in the baseline value of PASI and DLQI in the treatment group showed a significant difference compared with the control group (p < .05). The pathological changes of psoriasis skin and the expression of IL-17, IL-23, TNF-α in the psoriasis skin were improved in the treatment group. No serious adverse events occurred. CONCLUSION: The skin lesions in psoriasis patients with type 2 diabetes were significantly improved after treatment with liraglutide, which may be related to the inhibition of the expression of inflammatory factors such as IL-23, IL-17, and TNF-α.
Assuntos
Diabetes Mellitus Tipo 2 , Liraglutida , Psoríase , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/tratamento farmacológico , Receptor do Peptídeo Semelhante ao Glucagon 1/agonistas , Humanos , Interleucina-17 , Interleucina-23 , Liraglutida/uso terapêutico , Psoríase/complicações , Psoríase/tratamento farmacológico , Resultado do Tratamento , Fator de Necrose Tumoral alfaRESUMO
AIM: To assess the efficacy and safety of insulin degludec/liraglutide (IDegLira) versus insulin degludec (degludec) in Chinese people with type 2 diabetes (T2D) treated with basal insulin. MATERIALS AND METHODS: In DUAL II China, a randomized, double-blinded, multicentre, treat-to-target trial, Chinese adults with T2D and HbA1c of 7.5% or more on basal insulin and metformin, with or without other oral antidiabetic drugs (OADs), were randomized 2:1 to 26 weeks of treatment with either IDegLira (max. dose 50 U degludec/1.8 mg liraglutide) or degludec (max. 50 U/day), respectively, combined with metformin. At 26 weeks, superiority of IDegLira over degludec was assessed for change in HbA1c (primary endpoint), and body weight and number of severe or blood glucose (BG)-confirmed hypoglycaemic episodes (confirmatory secondary endpoints). RESULTS: Overall, 453 participants were randomized to IDegLira (n = 302) or degludec (n = 151). Superiority was confirmed for IDegLira over degludec in HbA1c change (-1.9% vs. -1.0%, respectively, estimated treatment difference [ETD] [95% confidence interval]: -0.92% [-1.09; -0.75], P < .0001), body weight change (-0.7 vs. +0.4 kg, respectively, ETD [95% CI]: -1.08 kg [-1.63; -0.52], P = .0002) and severe or BG-confirmed hypoglycaemia (estimated rate ratio [95% CI]: 0.53 [0.30; 0.94], P = .0297). The odds of achieving HbA1c less than 7.0% without hypoglycaemia and/or weight gain were greater with IDegLira than degludec (P < .0001 for all). Daily insulin dose at 26 weeks was lower for IDegLira (34.3 U) than degludec (37.4 U) (P = .0014). No unexpected safety signals were observed. CONCLUSIONS: IDegLira may be an efficacious and well-tolerated treatment intensification option for Chinese people with T2D uncontrolled on basal insulin and OADs.
Assuntos
Diabetes Mellitus Tipo 2 , Liraglutida , Adulto , Glicemia , Diabetes Mellitus Tipo 2/tratamento farmacológico , Combinação de Medicamentos , Hemoglobinas Glicadas/análise , Humanos , Hipoglicemiantes/uso terapêutico , Insulina de Ação Prolongada , Liraglutida/uso terapêutico , Redução de PesoRESUMO
BACKGROUND: To assess the association of metformin monotherapy with the risk of all-cause deaths and cardiovascular deaths and events in type 2 diabetes patients in real clinical practice. METHODS: This retrospective, observational study comprised patients with type 2 diabetes initially treated with metformin or nonmetformin monotherapy over 2011-2016. Data were extracted from the National Healthcare Big Data database in Fuzhou, China. Propensity score matching (PSM) was performed, matching each patient on metformin to one on nonmetformin in terms of a set of covariates. The primary endpoint was all-cause death, and secondary endpoints were cardiovascular death, heart failure, and heart failure hospitalization. Covariate-adjusted associations of metformin use with all the endpoints were assessed by Cox proportional hazards models. RESULTS: Among 24,099 patients, 5491 were initially treated with metformin and 18,608 with nonmetformin. PSM yielded 5482 patients in each cohort. During a median follow-up of 2.02 years, we observed 110 and 211 deaths in the metformin and nonmetformin groups, respectively. Metformin was significantly associated with reduced risk of all-cause death (adjusted hazard ratio (aHR) 0.52, 95% confidence interval (CI) 0.39-0.69), cardiovascular death (aHR 0.63, 95% CI 0.43-0.91), and heart failure (aHR 0.61, 95% CI 0.52-0.73), whereas the reduced risk in heart failure hospitalization was not statistically significant (aHR 0.70, 95% CI 0.47-1.02). CONCLUSIONS: In this analysis of electronic health record data from a large database in China, metformin as first-line monotherapy greatly reduced the risk of all-cause death, cardiovascular death, and heart failure in diabetes patients as compared with nonmetformin medications.
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Doenças Cardiovasculares/mortalidade , Diabetes Mellitus Tipo 2/tratamento farmacológico , Insuficiência Cardíaca/epidemiologia , Hipoglicemiantes/uso terapêutico , Metformina/uso terapêutico , Mortalidade , Idoso , Benzamidas/uso terapêutico , Carbamatos/uso terapêutico , Causas de Morte , Inibidores da Dipeptidil Peptidase IV/uso terapêutico , Feminino , Inibidores de Glicosídeo Hidrolases/uso terapêutico , Hospitalização/estatística & dados numéricos , Humanos , Masculino , Pessoa de Meia-Idade , Nateglinida/uso terapêutico , Piperidinas/uso terapêutico , Modelos de Riscos Proporcionais , Estudos Retrospectivos , Compostos de Sulfonilureia/uso terapêutico , Tiazolidinedionas/uso terapêuticoRESUMO
Diabetic nephropathy (DN) is a common complication of diabetes, and a leading cause of end-stage renal disease. However, the pathogenesis that contributes to DKD is still not fully understood. Protein tyrosine phosphatase non-receptor type 14 (PTPN14), a non receptor tyrosine phosphatase, has numerous cellular events, such as inflammation and cell death. But its potential on DKD has not been investigated yet. In this study, we found that PTPN14 expression was markedly up-regulated in kidney samples of DKD patients, which were confirmed in diabetic mice and were clearly localized in glomeruli. The diabetic mouse model was established using streptozotocin (STZ) in wild type (WT) or PTPN knockout (KO) mice. After, STZ challenge, STZ mice displayed improved kidney functions. The results also showed that STZ-induced histological changes and podocyte injury in renal tissues, which were effectively alleviated by PTPN14 deletion. Moreover, PTPN14 deficiency significantly mitigated inflammatory response and fibrosis in glomeruli of STZ-challenged mice through restraining the activation of nuclear factor-κB (NF-κB) and transforming growth factor (TGF)-ß1 signaling pathways, respectively. The inhibitory effects of PTPN14 suppression on inflammation and fibrosis were confirmed in high glucose (HG)-incubated podocytes. We further found that thyroid receptor interactor protein 6 (TRIP6) expression was dramatically up-regulated in glomeruli of STZ-challenged mice, and was abolished by PTPN14 deletion, which was confirmed in HG-treated podocytes with PTPN14 knockdown. Intriguingly, our in vitro studies showed that PTPN14 directly interacted with TRIP6. Of note, over-expressing TRIP6 markedly abrogated the effects of PTPN14 silence to restrict inflammatory response and fibrosis in HG-incubated podocytes. Taken together, our findings demonstrated that targeting PTPN14 may provide feasible therapies for DKD treatment.
Assuntos
Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Nefropatias Diabéticas/metabolismo , Fibrose/prevenção & controle , Inflamação/prevenção & controle , Proteínas com Domínio LIM/metabolismo , Podócitos/metabolismo , Proteínas Tirosina Fosfatases não Receptoras/deficiência , Fatores de Transcrição/metabolismo , Animais , Nefropatias Diabéticas/patologia , Modelos Animais de Doenças , Humanos , Rim/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Podócitos/patologia , Proteínas Tirosina Fosfatases não Receptoras/metabolismoRESUMO
OBJECTIVES: The purpose of this study was to investigate the effect of liraglutide on obesity diabetic mice with psoriasiform skin inflammation. METHODS: Wild-type mice and db/db mice were randomly divided into five groups (n = 6): including the control group which received Vaseline, the imiquimod (IMQ)-induction group and the liraglutide-treatment group. The advanced treatment with liraglutide (0.3 mg/kg/d) for 4 weeks before IMQ induced psoriatic skin inflammation in the db/db + IMQ + Lira group. Basic parameters of diabetes, PASI, histopathology of skin, the expression of IL-17A, IL-23, IL-22, and TNF-α in the skin of back were measured. RESULTS: After IMQ induction, the psoriatic skin inflammation and pathological changes in the db/db + IMQ group were more serious than those in the WT + IMQ group. The glucose metabolism and insulin resistance of in the db/db + IMQ + Lira group were significantly improved, Psoriasis Area and Severity Index (PASI) was significantly reduced, and the protein and mRNA expressions of IL-23, IL-17, IL-22, and TNF-α in the back skin tissues were decreased. CONCLUSIONS: Liraglutide can improve psoriasis skin lesions of obese diabetic mice, and the mechanism may be related to the inhibition of the expression of IL-23, IL-17, IL-22, and TNF-α through the IL-23/Th-17 pathway.
Assuntos
Interleucina-17 , Interleucina-23 , Liraglutida , Psoríase , Animais , Diabetes Mellitus Experimental/complicações , Modelos Animais de Doenças , Inflamação , Liraglutida/uso terapêutico , Camundongos , Camundongos Obesos , Obesidade/complicações , Psoríase/tratamento farmacológico , PeleRESUMO
This 24-week, double-blind, placebo-controlled, phase III trial evaluated the efficacy and safety of linagliptin in 206 Chinese patients with inadequately controlled (glycated haemoglobin [HbA1c] 7.5%-10.0%) type 2 diabetes mellitus (T2DM) receiving insulin (basal or premixed) ± metformin. Patients were randomized (1:1) to receive linagliptin 5 mg/d or placebo. The decrease from baseline in HbA1c (primary endpoint) was greater with linagliptin than with placebo (-0.61% vs. -0.20%, adjusted mean difference -0.40%; P = 0.0016). Linagliptin demonstrated significantly greater improvement in 2-hour postprandial glucose (-1.77 mmol/L [-31.95 mg/dL]; P < 0.001), and a numerical reduction in fasting plasma glucose (-0.34 mmol/L [-6.2 mg/dL]; P = 0.2241) versus placebo. Proportionally more patients on linagliptin achieved a HbA1c reduction of ≥0.5% versus those on placebo (odds ratio 2.293, P < 0.01). Adverse events in both groups were similar, with no new safety findings or clinically relevant changes in body weight. Among investigator-defined hypoglycaemic events (linagliptin: 17.3%; placebo: 12.7%; odds ratio 1.48, P = 0.337), none were severe. In Chinese patients with T2DM, linagliptin add-on to insulin improved glycaemic control and was well tolerated, without increased risk of hypoglycaemia or weight gain.
Assuntos
Diabetes Mellitus Tipo 2 , Linagliptina , Glicemia , China , Diabetes Mellitus Tipo 2/tratamento farmacológico , Método Duplo-Cego , Quimioterapia Combinada , Hemoglobinas Glicadas/análise , Humanos , Hipoglicemiantes/efeitos adversos , Insulina/uso terapêutico , Linagliptina/uso terapêutico , Resultado do TratamentoRESUMO
BACKGROUND: Type 2 diabetes mellitus is closely related to nonalcoholic fatty liver disease(NAFLD). More and more attention has been paid to the efficacy of liraglutide in the treatment of NAFLD, but the clinical evidence is still insufficient. OBJECTIVE: The purpose of this study was to use proton magnetic resonance spectroscopy (H-MRS) assessment of metformin alone poor blood glucose control of obese patients type 2 diabetes with NAFLD, added with insulin glargine, liraglutide or placebo effect in improving the fatty liver. METHODS: This is a 26-week, single-center, prospective, randomized placebo-controlled study. From September 2016 to July 2018, 128 patients with type 2 diabetes and NAFLD were enrolled in the China joint logistics team 900 hospital. The primary endpoints were the changes in intrahepatic content of lipid (IHCL), abdominal adiposity [subcutaneous adipose tissue (SAT) and visceral adipose tissue (VAT)], from baseline to week 26 (end of treatment) and the changes in liraglutide group or insulin glargine group versus change in placebo group. Secondary endpoints included the changes in liver function (AST and ALT), glycemia (HbA1c and FPG), body weight, and BMI. RESULTS: A total of 96 patients with type 2 diabetes and NAFLD under inadequate glycemic control by metformin were randomized (1:1:1) to receive add-on insulin glargine, liraglutide, or placebo. After 26 weeks of treatment, compared to the placebo group, in the liraglutide and insulin glargine groups, IHCL significantly decreased from baseline to week 26 (liraglutide 26.4% ± 3.2% to 20.6% ± 3.9%, P < 0.05; insulin glargine 25.0% ± 4.3% to 22.6% ± 5.8%, P > 0.05). SAT and VAT decreased significantly in the liraglutide group and in the insulin glargine group (P < 0.05). ΔSAT and ΔVAT were greater with liraglutide than insulin glargine, they were significantly different between the two groups (ΔSAT, -36 vs. - 24.5, P < 0.05; and ΔVAT, -47 vs. - 16.6, P > 0.05). In the liraglutide group, AST, ALT, and HOMA-IR decreased significantly from baseline. There was no significant difference in glucose-lowering among the three groups. During the treatment, the safety of the three groups performed well. CONCLUSION: Compared with placebo, treatment with liraglutide plus an adequate dose of metformin (2000 g/ day) for 26 weeks is more effective in reducing IHCL, SAT and VAT in patients with type 2 diabetes and NAFLD. And it has additional advantages in weight loss, waist circumference reduction and liver function improvement.
Assuntos
Diabetes Mellitus Tipo 2/tratamento farmacológico , Hipoglicemiantes/administração & dosagem , Insulina Glargina/administração & dosagem , Liraglutida/administração & dosagem , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Obesidade/tratamento farmacológico , Adulto , Glicemia/análise , Glicemia/efeitos dos fármacos , Peso Corporal/efeitos dos fármacos , China , Diabetes Mellitus Tipo 2/sangue , Quimioterapia Combinada , Feminino , Hemoglobinas Glicadas/análise , Hemoglobinas Glicadas/efeitos dos fármacos , Humanos , Gordura Intra-Abdominal/efeitos dos fármacos , Fígado/efeitos dos fármacos , Masculino , Metformina/uso terapêutico , Pessoa de Meia-Idade , Estudos Prospectivos , Gordura Subcutânea/efeitos dos fármacos , Resultado do Tratamento , Redução de Peso/efeitos dos fármacosRESUMO
Studies have shown that liraglutide, or human umbilical cord mesenchymal stem cell (hUC-MSCs) can improve non-alcoholic fatty liver disease (NAFLD). However there have been no studies on the combination of the two used to treat NAFLD. This study aimed to explore the therapeutic effects of combination of liraglutide and hUC-MSCs on liver injury in rats with type 2 diabetes mellitus (T2DM) and NAFLD, and further investigate their mechanisms. Sprague Dawley rats fed by a high fat and high sucrose diet were randomly divided into 5 groups, including NC group, T2DM/NAFLD group, liraglutide group (treated with liraglutide, 200 µg/kg, twice daily for 8 weeks), hUC-MSCs group (treated with hUC-MSCs at the first and fifth weeks), liraglutidï¼hUC-MSCs group (treated with liraglutide and hUC-MSCs). Liver tissue was procured for histological examination, real-time qRT-PCR and Western blot analysis. After treatment, liraglutide and hUC-MSCs reduced serum ALT and AST levels, alleviate liver inflammation and improved liver histopathology. The expressions of inflammatory cytokines, TLR4 and NF-κB in serum and liver were significantly inhibited, particularly in the combination treatment group. Eight weeks after liraglutide or hUC-MSCs administration, FBG, HbA1c, HOMA-IR, ALT, AST, Liver wet eight and hepatic TLR4, NF-κB, IL-6, TNF-α, 8-OHdG mRNA and proteins were significantly decreased, and the levels of SOD expression were significantly increased in three treatment groups compared with T2DM/NAFLD group. This study suggests that liraglutide in combination with hUC-MSCs could significantly improve glycolipid metabolism, insulin resistance and liver injury in T2DM/NAFLD rats. Its mechanism may be related to the down-regulation of the TLR4/NF-κB inflammatory pathway and improvement in oxidative stress.
Assuntos
Diabetes Mellitus Tipo 2/complicações , Inflamação/patologia , Liraglutida/farmacologia , Neoplasias Hepáticas/terapia , Células-Tronco Mesenquimais/citologia , NF-kappa B/metabolismo , Hepatopatia Gordurosa não Alcoólica/complicações , Estresse Oxidativo , Receptor 4 Toll-Like/metabolismo , 8-Hidroxi-2'-Desoxiguanosina/metabolismo , Animais , Terapia Combinada , Citocinas/sangue , Citocinas/genética , Diabetes Mellitus Tipo 2/sangue , Humanos , Fígado/patologia , Fígado/ultraestrutura , Neoplasias Hepáticas/sangue , Neoplasias Hepáticas/patologia , Masculino , Transplante de Células-Tronco Mesenquimais , Células-Tronco Mesenquimais/efeitos dos fármacos , NF-kappa B/genética , Hepatopatia Gordurosa não Alcoólica/sangue , Estresse Oxidativo/efeitos dos fármacos , Ratos Sprague-Dawley , Superóxido Dismutase/genética , Superóxido Dismutase/metabolismo , Receptor 4 Toll-Like/genética , Cordão Umbilical/citologiaRESUMO
BACKGROUND: Insulin therapy is poorly accepted by patients with type 2 diabetes mellitus (T2DM). A needle-free insulin injector has been developed for patients who fear injections or are reluctant to initiate insulin therapy when it is clearly indicated. The objective of this trial was to evaluate the glucose-lowering effect, tolerability, patient satisfaction and compliance with insulin treatment via a needle-free insulin injector (NFII) compared with insulin treatment via a conventional insulin pen (CIP) in patients with T2DM. METHODS: A total of 427 patients with T2DM were enrolled in a prospective, multicenter, randomized, open-label study, and were randomly assigned 1:1 to receive 16 weeks' treatment with basal insulin or premixed insulin administered either by a NFII or CIP. TRIAL REGISTRATION: ClinicalTrials.gov (NCT03243903). FINDINGS: In the 412 patients who completed the study, the adjusted mean reduction of HbA1c from baseline at week 16 in the NFII group was 0.55% (95% CI -0.71, -0.39), which was non-inferior and statistically superior to the HbA1c reduction in the CIP group (0.26%, 95% CI -0.42, -0.11). Patients in the NFII group showed significantly higher treatment satisfaction scores than those in the CIP group (mean scores, 8.17 ± 1.78 vs. 7.21 ± 2.22, respectively; p<0.0001). The occurrence of hypoglycemia was similar in the two groups, and the NFII group showed reduced incidences of skin scratches, indurations and lower VAS pain scores. INTERPRETATION: Insulin therapy through needle-free injector showed a non-inferior glycemic-lowering effect and a significantly enhanced level of patient satisfaction with insulin treatment compared with conventional insulin therapy through needle injections. In addition, the needle-free injector also had a better safety profile. FUNDING: This study were funded by Beijing QS Medical Technology Co., Ltd, as well as The Major Chronic Non-communicable Disease Prevention and Control Research.
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Objective: DBPR108, a novel dipeptidyl-peptidase-4 inhibitor, has shown great antihyperglycemic effect in animal models. This study was to evaluate the efficacy and safety of DBPR108 monotherapy in type 2 diabetes mellitus (T2DM).Methods: This was a 12-week, double-blind, placebo-controlled phase II clinical trial. The newly diagnosed or inadequately controlled untreated T2DM patients were randomized to receive 50, 100, 200 mg DBPR108 or placebo in a ratio of 1:1:1:1. The primary efficacy outcome was HbA1c change from baseline to week 12. Relevant secondary efficacy parameters and safety were assessed. The clinical trial registration is NCT04124484.Results: Overall, 271 of the 276 randomized patients, who received 50 mg (n = 68), 100 mg (n = 67), 200 mg (n = 69) DBPR108 or placebo (n = 67), were included in full analysis set. At week 12, HbA1c change from baseline was -0.04 ± 0.77 in placebo group, -0.51 ± 0.71, -0.75 ± 0.73, and -0.57 ± 0.78 (%, p < .001 vs. placebo) in 50, 100, and 200 mg DBPR108 groups, respectively. Since week 4, DBPR108 monotherapy resulted in significant improvements in secondary efficacy parameters. At end of 12-week treatment, the goal of HbA1c ≤7% was achieved in 29.85, 58.82, 55.22, and 47.83% of the patients in placebo, 50, 100, and 200 mg DBPR108 groups, respectively. The incidence of adverse events did not show significant difference between DBPR108 and placebo except mild hypoglycemia in DBPR108 200 mg group.Conclusions: The study results support DBPR108 100 mg once daily as the primary dosing regimen for T2DM patients in phase III development program.
Assuntos
Diabetes Mellitus Tipo 2/tratamento farmacológico , Inibidores da Dipeptidil Peptidase IV/uso terapêutico , Hipoglicemiantes/uso terapêutico , Adulto , Idoso , Método Duplo-Cego , Feminino , Hemoglobinas Glicadas/análise , Humanos , Hipoglicemiantes/efeitos adversos , Masculino , Pessoa de Meia-Idade , Fatores de TempoRESUMO
INTRODUCTION: China has the largest number of diabetic patients in the world. In the past 2 decades, the prevalence of diabetes in China has increased dramatically, and the current status of diabetes control in the diabetic population is not satisfactory. Although insulin is currently recognized in diabetes treatment guidelines as the therapeutic option for patients not adequately controlled by diet/exercise and oral agents, the proportion of patients with type 2 diabetes using insulin is still very low, and the time when insulin therapy is initiated is relatively late. In using insulin injections, concerns about the complexity of the treatment regimen, a fear of needles, and other psychological barriers can affect insulin treatment, impacting on patient compliance and potentially resulting in a poor treatment response. Another type of insulin injection device that has become available recently, the needle-free injector, is now being used in clinical practice because of its unique features and patients' injection experiences. The aims of this study are to investigate the efficacy and safety of the needle-free injector-based insulin treatment in blood glucose control in patients with type 2 diabetes, as compared with a conventional needle-based insulin treatment, and to evaluate patient satisfaction with the different insulin delivery methods. METHODS AND PLANNED OUTCOMES: A prospective, multicenter, randomized, open-label, parallel-group clinical trial was designed and implemented in China. A total of 420 patients with type 2 diabetes from ten research centers will be enrolled in the study. The primary efficacy endpoint is the change in the glycosylated hemoglobin (HbA1c) level from baseline to after 16 weeks of treatment after randomization. Secondary efficacy endpoints include measurements of blood glucose concentrations, the rate of achieving the target HbA1c level of less than 7%, patients' quality-of-life (as determined by the SF-36 questionnaire), the insulin dose administered, compliance with insulin therapy, and patients' satisfaction with their injection device. ETHICS AND DISSEMINATION: The study was approved by the Independent Ethics Committee (IEC) of Peking University Peoples Hospital and was conducted in accordance with the moral, ethical, and scientific principles of the declaration of Helsinki and the provisions of good clinical practice (GCP) in China. Written informed consent will be obtained from all participants before any study-related procedures are implemented. It is hoped that the study will provide evidence for the clinical application of the needle-free injector by providing data on its efficacy and safety, as compared with a conventional insulin pen, in the Chinese type 2 diabetes population. When available, the results will be published in an international peer-reviewed journal. TRIAL REGISTRATION: ClinicalTrials.gov Identifier, NCT03243903. Registration date, August 9, 2017. FUNDING: Beijing QS Medical Technology Co., Ltd.
Assuntos
Povo Asiático/psicologia , Diabetes Mellitus Tipo 2/tratamento farmacológico , Hipoglicemiantes/uso terapêutico , Sistemas de Infusão de Insulina , Insulina/administração & dosagem , Agulhas , Satisfação do Paciente/estatística & dados numéricos , Adolescente , Adulto , Idoso , China/epidemiologia , Diabetes Mellitus Tipo 2/epidemiologia , Feminino , Humanos , Hipoglicemiantes/administração & dosagem , Masculino , Pessoa de Meia-Idade , Segurança do Paciente , Estudos Prospectivos , Inquéritos e Questionários , Resultado do Tratamento , Adulto JovemRESUMO
AIMS: To assess the efficacy and safety of twice-daily insulin degludec/insulin aspart (IDegAsp) versus biphasic insulin aspart 30 (BIAsp 30) twice daily, both ± metformin, in Chinese adults (N = 543) with type 2 diabetes (T2D) inadequately controlled on premixed/self-mixed or basal insulin ± metformin. MATERIALS AND METHODS: We conducted a 26-week, phase III, open-label, treat-to-target, 2:1 randomized trial. Hierarchical testing was used with non-inferiority of glycated haemoglobin (HbA1c) change from baseline to week 26 as the primary endpoint and superiority for the confirmatory secondary endpoints which were as follows: change from baseline in fasting plasma glucose (FPG); nocturnal confirmed hypoglycaemic episodes (12:01-5:59 am, inclusive); total confirmed hypoglycaemic episodes (severe or plasma glucose <3.1 mmol/L with/without symptoms); body weight; and percentage of responders (HbA1c <53 mmol/mol [<7.0%]) without confirmed hypoglycaemic episodes. RESULTS: Non-inferiority for change from baseline to week 26 in HbA1c and superiority of IDegAsp twice daily versus BIAsp 30 twice daily for change in FPG, nocturnal confirmed and total confirmed hypoglycaemic episodes, was demonstrated. Estimated rates of nocturnal confirmed and total confirmed hypoglycaemic episodes were 47% and 43% lower, respectively, with IDegAsp twice daily versus BIAsp 30 twice daily. Superiority for change in body weight was not confirmed. Participants were more likely to reach the HbA1c goal of <53 mmol/mol (<7.0%) without confirmed hypoglycaemia with IDegAsp twice daily versus BIAsp 30 twice daily by trial end. No new safety signals were identified. CONCLUSIONS: The efficacy and safety of IDegAsp in Chinese patients with T2D was demonstrated, confirming results from international trials.
Assuntos
Insulinas Bifásicas , Diabetes Mellitus Tipo 2/tratamento farmacológico , Hipoglicemiantes , Insulina Aspart , Insulina Isófana , Insulina de Ação Prolongada , Idoso , Insulinas Bifásicas/efeitos adversos , Insulinas Bifásicas/uso terapêutico , Glicemia/análise , Peso Corporal , China , Combinação de Medicamentos , Feminino , Hemoglobinas Glicadas/análise , Humanos , Hipoglicemia/induzido quimicamente , Hipoglicemia/epidemiologia , Hipoglicemiantes/efeitos adversos , Hipoglicemiantes/uso terapêutico , Insulina Aspart/efeitos adversos , Insulina Aspart/uso terapêutico , Insulina Isófana/efeitos adversos , Insulina Isófana/uso terapêutico , Insulina de Ação Prolongada/efeitos adversos , Insulina de Ação Prolongada/uso terapêutico , Masculino , Pessoa de Meia-IdadeRESUMO
BACKGROUND: It has been reported that GLP-1 analogue can improve the skin lesions of psoriasis. However further research is needed to confirm that finding. OBJECTIVE: The study can provide further data regarding the efficacy and safety of GLP-1 analogue liraglutide in the treatment of psoriasis patients with type 2 diabetes. METHODS: We recruit 7 psoriasis patients with type 2 diabetes, and use hypodermic injection with liraglutide1.8â¯mg. In 12â¯weeks of treatment, we estimate the difference of before and after respectively, likeBMI, waist circumference, fasting blood glucose, fasting C-peptide, HbA1c, blood lipid levels, CRP, PASI, DLQI, skin tissue and pathological analysis of psoriasis. RESULTS: After 12â¯weeks of treatment, the mean value of PASI decreased from 15.7⯱â¯11.8 to 2.2⯱â¯3.0 (Pâ¯=â¯0.03), while the DLQI decreased from 21.8⯱â¯6 to 4.1⯱â¯3.9 (Pâ¯=â¯0.001). HbA1c was significantly improved after 12â¯weeks of treatment, decreased to 6.4⯱â¯0.8% (Pâ¯=â¯0.04), the BMI decreased to 21⯱â¯3â¯kgâ¯m-2 (Pâ¯<â¯0.01), and the waist circumference was also significantly improved to 83⯱â¯1â¯cm (Pâ¯<â¯0.05). And 12â¯weeks after, the fasting C-peptide levels increased to 1.9⯱â¯0.5â¯ng/ml (Pâ¯=â¯0.006), HOMA - IR fell to 1.6⯱â¯0.6 (Pâ¯=â¯0.03). Histological analysis showed a reduction in epidermal thickness after treatment. The mean PASI decreased from 15.7 (1.5-31.3) to 2.0 (0.3-8.7) (Pâ¯=â¯0.03), the DLQI decreased from 22 (8-27) to 4 (0-10) (Pâ¯=â¯0.001). CONCLUSION: GLP-1 analogueliraglutide can improve the skin lesions of psoriasis patients with type 2 diabetes effectively, especially for extremely severe psoriasis patients. Its therapeutic effect may be related to anti-inflammatory, hypoglycemic and reducing weight.
Assuntos
Diabetes Mellitus Tipo 2/complicações , Peptídeo 1 Semelhante ao Glucagon/análogos & derivados , Hipoglicemiantes/uso terapêutico , Liraglutida/uso terapêutico , Psoríase/tratamento farmacológico , Idoso , Glicemia/análise , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , Estudos Prospectivos , Psoríase/etiologia , Psoríase/patologiaRESUMO
AIMS: The aim of this study was to investigate the effects of liraglutide on renal injury and the renal expression of FoxO1 in type 2 diabetic rats. METHODS: Type 2 diabetic rats model was induced by a high-sugar and high-fat diet and intraperitoneal injection of low-dose Streptozotocin (STZ) (30â¯mg/kg). Five weeks after STZ injection, diabetic rats were randomly treated with or without subcutaneous injection of liraglutide (0.2â¯mg/kg/12â¯h) for eight weeks. Diabetes-related physical and biochemical indicators, renal histopathological and ultrastructural changes, the expression of renal transforming growth factor beta-1 (TGF-ß1), fibronectin (FN), type IV collagen (Col IV), protein kinase B (Akt), forkhead box protein O1 (FoxO1) and manganese superoxide dismutase (MnSOD) were measured. RESULTS: Rats in DN group showed a significant increase in fasting blood glucose, HbA1c, kidney to body weight index, serum creatinine (Scr), blood urea nitrogen (BUN), urinary albumin excretion, mesangial matrix index, glomerular basement membrane (GBM) thickening, podocyte foot process fusion, the mRNA and protein levels of renal TGF-ß1, FN and Col IV and a dramatic decrease in the mRNA and protein levels of renal MnSOD, all of which were significantly ameliorated by liraglutide. In addition, liraglutide also increased the expression of FoxO1 mRNA and reduced renal phosphorylation levels of Akt and FoxO1 protein. CONCLUSIONS: These results suggest that liraglutide may exert a renoprotective effect by a FoxO1-mediated upregulation of renal MnSOD expression in the early DKD.
Assuntos
Diabetes Mellitus Experimental/tratamento farmacológico , Nefropatias Diabéticas/tratamento farmacológico , Proteína Forkhead Box O1/genética , Hipoglicemiantes/uso terapêutico , Rim/patologia , Liraglutida/uso terapêutico , Animais , Nefropatias Diabéticas/metabolismo , Proteína Forkhead Box O1/metabolismo , Hipoglicemiantes/farmacologia , Liraglutida/farmacologia , Masculino , RatosRESUMO
BACKGROUND: Limited information exists regarding the efficacy of pregabalin in Chinese patients with painful diabetic peripheral neuropathy (pDPN). METHODS: An 11-week double-blind placebo-controlled trial was performed in Chinese pDPN patients randomized (1 : 1) to 300 mg/day pregabalin or placebo. The primary outcome was change from baseline to endpoint in mean pain score (MPS; 0, no pain; 10, worst possible pain; using the mean of the last seven daily pain scores). Secondary outcomes included weekly MPS and responder status (MPS reduced by ≥30% or ≥50% vs baseline). Subgroup analysis assessed patients with severe (≥7) baseline MPS. Adverse events (AEs) were reported. RESULTS: In all, 620 patients were randomized (pregabalin, n = 313; placebo, n = 307). Improvement in MPS with pregabalin versus placebo was not significant (P = 0.0559). Post hoc sensitivity analyses, excluding one patient/site due to Good Clinical Practice (GCP) non-compliance, showed pregabalin significantly improved MPS when excluding the patient (P = 0.0448) or site (P = 0.0142). Pregabalin significantly improved weekly MPS (P = 0.0164) and ≥50% responders at endpoint (P = 0.0384). Improvement in proportion of ≥30% responders, impression of change, pain intensity, and sleep did not differ significantly between the treatment groups. In the severe pDPN subpopulation, pregabalin significantly improved MPS versus placebo (P = 0.0040). The most commonly reported AE was dizziness (9.6% vs 3.9% with placebo). CONCLUSIONS: Pregabalin did not significantly improve the primary measure of pain in the trial. Significant reductions in MPS were observed when excluding the GCP non-compliant patient/site and in the severe pDPN subpopulation. Pregabalin was well tolerated in Chinese pDPN patients.
Assuntos
Bloqueadores dos Canais de Cálcio/uso terapêutico , Diabetes Mellitus Tipo 1/complicações , Diabetes Mellitus Tipo 2/complicações , Neuropatias Diabéticas/tratamento farmacológico , Pregabalina/uso terapêutico , Adolescente , Adulto , Idoso , Povo Asiático , Biomarcadores/metabolismo , Neuropatias Diabéticas/etiologia , Método Duplo-Cego , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Medição da Dor , Segurança , Resultado do Tratamento , Adulto JovemRESUMO
AIMS: To assess the effects on glycaemic control of lixisenatide vs placebo as add-on treatment to basal insulin (BI) ± metformin and effects on glycated haemoglobin (HbA1c) reduction in patients with insufficiently controlled type 2 diabetes (T2D). METHODS: Patients (n = 448) with inadequately controlled T2D were randomized (1:1) to lixisenatide or placebo as add-on to BI ± metformin for 24 weeks after an 8-week run-in phase, during which BI was titrated to a target self-monitored plasma glucose (SMPG; 4.4-5.6 mmol/L). The primary endpoint was absolute change in HbA1c from baseline to week 24. Secondary efficacy endpoints included: percentage of responders; changes in 2-hour postprandial plasma glucose (PPG); 7-point SMPG (daily average); body weight (BW); total daily BI dose; fasting plasma glucose; and safety assessments. RESULTS: Baseline demographics were similar in the two treatment groups. After insulin optimization during run-in, lixisenatide was superior to placebo in mean change from baseline (7.9% [standard deviation {s.d.}, 0.66] and 7.9% [0.70], respectively) to week 24 in HbA1c (least squares mean [standard error {s.e.}] change -0.62% [0.09] vs -0.11% [0.09]; P < .0001, respectively) and higher proportions of patients achieved HbA1c targets. Two-hour PPG, daily mean SMPG and mean BW were reduced further and daily BI dose was lower with lixisenatide than placebo (-1.12 kg vs 0.04 kg [P < .0001]; -3.0 U vs -1.9 U [P = .0033], respectively). Treatment-emergent adverse events were greater with lixisenatide than placebo (63.8% vs 40.8%, respectively). The incidence of symptomatic hypoglycaemia was similar (lixisenatide 15.6% vs placebo 13.5%). CONCLUSIONS: In Asian patients insufficiently controlled on BI ± metformin, lixisenatide was superior to placebo in glycaemic control, with a tolerability profile in line with other glucagon-like peptide-1 receptor agonists. CLINICAL TRIAL NUMBER: NCT01632163 (clinicaltrials.gov).
Assuntos
Diabetes Mellitus Tipo 2/tratamento farmacológico , Receptor do Peptídeo Semelhante ao Glucagon 1/agonistas , Hiperglicemia/prevenção & controle , Hipoglicemia/prevenção & controle , Hipoglicemiantes/uso terapêutico , Resistência à Insulina , Peptídeos/uso terapêutico , Adulto , Ásia/epidemiologia , Glicemia/análise , Automonitorização da Glicemia , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/etnologia , Diabetes Mellitus Tipo 2/metabolismo , Método Duplo-Cego , Quimioterapia Combinada/efeitos adversos , Feminino , Seguimentos , Receptor do Peptídeo Semelhante ao Glucagon 1/metabolismo , Hemoglobinas Glicadas/análise , Humanos , Hipoglicemia/induzido quimicamente , Hipoglicemia/epidemiologia , Hipoglicemiantes/administração & dosagem , Hipoglicemiantes/efeitos adversos , Incidência , Insulina/administração & dosagem , Insulina/uso terapêutico , Resistência à Insulina/etnologia , Masculino , Pessoa de Meia-Idade , Peptídeos/efeitos adversos , Período Pós-PrandialRESUMO
OBJECTIVES: Type 2 diabetes mellitus (T2DM) increases the risk of brain atrophy and dementia. We aimed to elucidate deep grey matter (GM) structural abnormalities and their relationships with T2DM cognitive deficits by combining region of interest (ROI)-based volumetry, voxel-based morphometry (VBM) and shape analysis. METHODS: We recruited 23 T2DM patients and 24 age-matched healthy controls to undergo T1-weighted structural MRI scanning. Images were analysed using the three aforementioned methods to obtain deep GM structural shapes and volumes. Biochemical and cognitive assessments were made and were correlated with the resulting metrics. RESULTS: Shape analysis revealed that T2DM is associated with focal atrophy in the bilateral caudate head and dorso-medial part of the thalamus. ROI-based volumetry only detected thalamic volume reduction in T2DM when compared to the controls. No significant between-group differences were found by VBM. Furthermore, a worse performance of cognitive processing speed correlated with more severe GM atrophy in the bilateral dorso-medial part of the thalamus. Also, the GM volume in the bilateral dorso-medial part of the thalamus changed negatively with HbA1c. CONCLUSIONS: Shape analysis is sensitive in identifying T2DM deep GM structural abnormalities and their relationships with cognitive impairments, which may greatly assist in clarifying the neural substrate of T2DM cognitive dysfunction. KEY POINTS: ⢠Type 2 diabetes mellitus is accompanied with brain atrophy and cognitive dysfunction ⢠Deep grey matter structures are essential for multiple cognitive processes ⢠Shape analysis revealed local atrophy in the dorso-medial thalamus and caudatum in patients ⢠Dorso-medial thalamic atrophy correlated to cognitive processing speed slowing and high HbA1c. ⢠Shape analysis has advantages in unraveling neural substrates of diabetic cognitive deficits.