GLP-1 and GIP promote insulin secretion from pancreatic β-cells by inducing intracellular signals such as Ca2+ and cAMP. Metformin primarily acts by inhibiting glucogenesis in the liver and promoting glucose metaboli...GLP-1 and GIP promote insulin secretion from pancreatic β-cells by inducing intracellular signals such as Ca2+ and cAMP. Metformin primarily acts by inhibiting glucogenesis in the liver and promoting glucose metabolism in the muscle. It is used as a concomitant drug with the incretin in the treatment of T2D. We focused on intracellular signals under various glucose concentrations and assessed the effects of metformin on incretin signaling in MIN6 β-cells. Metformin inhibited incretin-induced [Ca2+]i in the presence of 5.5 mM glucose but not 16.7 mM glucose. In accordance with low [Ca2+]i, insulin secretion from MIN6 cells declined, despite enhanced incretin-induced cAMP production. Abundant expressions of Adcy 6 and 9, which are negatively controlled by Ca2+ signals, were detected in MIN6 cells. Thus, increasing cAMP production was associated with the inhibition of Ca2+ mobilization by metformin. However, we show that metformin controls insulin secretion by inhibiting incretin-mediated [Ca2+]i under normoglycemic conditions.展开更多
Background: In order to discover new strategies to replace antibiotics in the post-antibiotic era in meat-type chicken production, two new synbiotics were tested:(Lactobacillus salivarius IBB3154 plus galactooligosacc...Background: In order to discover new strategies to replace antibiotics in the post-antibiotic era in meat-type chicken production, two new synbiotics were tested:(Lactobacillus salivarius IBB3154 plus galactooligosaccharide(Syn1) and Lactobacillus plantarum IBB3036 plus raffinose family oligosaccharides(Syn2).Methods: The synbiotics were administered via syringe, using a special automatic system, into the egg air chamber of Cobb 500 broiler chicks on the 12 thday of egg incubation(2 mg of prebiotics + 105 cfu bacteria per egg).Hatched roosters(total 2,400) were reared on an experimental farm, kept in pens(75 animals per pen), with free access to feed and water. After 42 d animals were slaughtered. Blood serum, pancreas, duodenum and duodenum content were collected.Results: Syn2 increased trypsin activity by 2.5-fold in the pancreas and 1.5-fold in the duodenal content. In the duodenum content, Syn2 resulted in ca 30% elevation in lipase activity and 70% reduction in amylase activity.Syn1 and Syn2 strongly decreased expression of m RNA for GLP-1 and GIP in the duodenum and for GLP-1 receptors in the pancreas. Simultaneously, concentrations of the incretins significantly diminished in the blood serum(P < 0.05). The decreased expression of incretins coincides with changed activity of digestive enzymes in the pancreas and in the duodenal content. The results indicate that incretins are involved in the action of Syn1 and Syn2 or that they may even be their target. No changes were observed in key hormones regulating metabolism(insulin, glucagon, corticosterone, thyroid hormones, and leptin) or in metabolic indices(glucose,NEFA, triglycerides, cholesterol). Additionally, synbiotics did not cause significant changes in the activities of alanine and aspartate aminotransferases in broiler chickens. Simultaneously, the activity of alkaline phosphatase and gamma glutamyl transferase diminished after Syn2 and Syn1, respectively.Conclusion: The selected synbiotics may be used as in ovo additives for broiler chickens, and Syn2 seems to improve their potential digestive proteolytic and lipolytic ability. Our results suggest that synbiotics can be directly or indirectly involved in incretin secretion and reception.展开更多
目的:探讨胰高血糖素样肽-1(GLP-1)蛋白对帕金森病氧化应激损伤的保护作用及机制。方法:36只8周龄C57BL/6雄性小鼠随机平分为三组(模型组、利拉鲁肽组与GLP-1组)。所有小鼠都给予建立帕金森病模型,模型组在建模过程中给予0.1 ml 0.9%氯...目的:探讨胰高血糖素样肽-1(GLP-1)蛋白对帕金森病氧化应激损伤的保护作用及机制。方法:36只8周龄C57BL/6雄性小鼠随机平分为三组(模型组、利拉鲁肽组与GLP-1组)。所有小鼠都给予建立帕金森病模型,模型组在建模过程中给予0.1 ml 0.9%氯化钠溶液注射,利拉鲁肽组在给予利拉鲁肽腹腔注射25 nmol/(kg·d),GLP-1组在建给予GLP-1/GIP双受体激动剂(DA3-CH)腹腔注射25 nmol/(kg·d),连续治疗7 d。结果:三组建模第7天的转棒停留时间、牵拉肌张力评分都低于建模第1天(均P<0.05),利拉鲁肽组与GLP-1组高于模型组(P<0.05),GLP-1组高于利拉鲁肽组(均P<0.05)。利拉鲁肽组与GLP-1组建模第7天的血清Chi3l1含量、脑组织IBA-1和胶质纤维酸性蛋白(GFAP)相对表达水平低于模型组(均P<0.05),GLP-1组低于利拉鲁肽组(P<0.05)。结论:GLP-1蛋白在帕金森病小鼠的应用能缓解氧化应激损伤,抑制血清Chi3l1与脑组织IBA-1、GFAP蛋白的表达,从而发挥神经保护作用。展开更多
Patients with Parkinson's disease(PD) have impaired insulin signaling in the brain. Incretin hormones, including glucagon-like peptide-1(GLP-1) and glucose-dependent insulinotropic polypeptide(GIP), can re-sensiti...Patients with Parkinson's disease(PD) have impaired insulin signaling in the brain. Incretin hormones, including glucagon-like peptide-1(GLP-1) and glucose-dependent insulinotropic polypeptide(GIP), can re-sensitize insulin signaling. In a recent phase II clinical trial, the first GLP-1 mimic, exendin-4, has shown reliable curative effect in patients with PD. DA-CH5 is a novel GLP-1/GIP receptor unimolecular coagonist with a novel peptide sequence added to cross the blood-brain barrier. Here we showed that both exendin-4 and DA-CH5 protected against 6-hydroxydopamine(6-OHDA) cytotoxicity, inhibited apoptosis, improved mitogenesis and induced autophagy flux in SH-SY5Y cells via activation of the insulin receptor substrate-1(IRS-1)/alpha serine/threonine-protein kinase(Akt)/c AMP response element-binding protein(CREB) pathway. We also found that DA-CH5(10 nmol/kg) daily intraperitoneal administration for 30 days post-lesion alleviated motor dysfunction in rats and prevented stereotactic unilateral administration of 6-OHDA induced dopaminergic neurons loss in the substantia nigra pars compacta. However, DA-CH5 showed curative effects in reducing the levels of α-synuclein and the levels of pro-inflammatory cytokines(tumor necrosis factor-α, interleukin-1β). It was also more effective than exendin-4 in inhibiting apoptotic process and protecting mitochondrial functions. In addition, insulin resistance was largely alleviated and the expression of autophagy-related proteins was upregulated in PD model rats after DA-CH5 treatment. These results in this study indicate DA-CH5 plays a therapeutic role in the 6-OHDAunilaterally lesioned PD rat model and is superior to GLP-1 analogue exendin-4. The study was approved by the Animal Ethics Committee of Shanxi Medical University of China.展开更多
目的在不同食物负荷情况下,观察阿卡波糖对T2DM患者血清胰升糖素样肽-1(GLP-1)和抑胃肽(GIP)水平的影响。方法新诊断T2DM患者32例,随机分为OGTT组和混合餐试验(MIX)组,使用阿卡波糖片治疗共6周。在服药前1周、第一次服药及治疗6周后行O...目的在不同食物负荷情况下,观察阿卡波糖对T2DM患者血清胰升糖素样肽-1(GLP-1)和抑胃肽(GIP)水平的影响。方法新诊断T2DM患者32例,随机分为OGTT组和混合餐试验(MIX)组,使用阿卡波糖片治疗共6周。在服药前1周、第一次服药及治疗6周后行OGTT或MIX,试验时检测0、15、30、60、90、120 min PG、GIP、GLP-1。结果(1)OGTT组与MIX组均随机入组16例,平均年龄分别为(51.7±10.4)、(51.8±11.7)岁。(2)首次使用阿卡波糖治疗,MIX组负荷后PG、GIP均有下降,其中15、30、60、90、120 min PG,15、30、60、90 min GIP,PG、GIP曲线下面积(AUC)比较,差异有统计学意义(P<0.05);MIX组90 min GLP-1较治疗前升高(P<0.05)。OGTT组各点PG、GLP-1、GIP水平及AUC与治疗前比较,差异无统计学意义。(3)治疗6周后,MIX组负荷后PG较治疗前下降,GIP水平随着PG下降,在15、30、60、90 min时较治疗前下降(P<0.05)。MIX组90 min GLP-1较治疗前升高(P<0.05)。OGTT组各点GLP-1、GIP水平及AUC与治疗前比较,差异无统计学意义。结论在不同种类糖负荷下,阿卡波糖对肠促胰岛素的影响可能不同。在复合碳水化合物负荷下,阿卡波糖可能影响GLP-1晚相分泌水平,而GIP可随PG水平的下降而降低。展开更多
文摘GLP-1 and GIP promote insulin secretion from pancreatic β-cells by inducing intracellular signals such as Ca2+ and cAMP. Metformin primarily acts by inhibiting glucogenesis in the liver and promoting glucose metabolism in the muscle. It is used as a concomitant drug with the incretin in the treatment of T2D. We focused on intracellular signals under various glucose concentrations and assessed the effects of metformin on incretin signaling in MIN6 β-cells. Metformin inhibited incretin-induced [Ca2+]i in the presence of 5.5 mM glucose but not 16.7 mM glucose. In accordance with low [Ca2+]i, insulin secretion from MIN6 cells declined, despite enhanced incretin-induced cAMP production. Abundant expressions of Adcy 6 and 9, which are negatively controlled by Ca2+ signals, were detected in MIN6 cells. Thus, increasing cAMP production was associated with the inhibition of Ca2+ mobilization by metformin. However, we show that metformin controls insulin secretion by inhibiting incretin-mediated [Ca2+]i under normoglycemic conditions.
基金supported by the European Union Seventh Framework Programme for research,technological development and demonstration as part of the ECO-FCE project under grant agreement No.311794partly funded by the Ministry of Science and Higher Education from funds for science in the years 2015–2016 allocated to an international co-financed project(no W171.PR/2015)
文摘Background: In order to discover new strategies to replace antibiotics in the post-antibiotic era in meat-type chicken production, two new synbiotics were tested:(Lactobacillus salivarius IBB3154 plus galactooligosaccharide(Syn1) and Lactobacillus plantarum IBB3036 plus raffinose family oligosaccharides(Syn2).Methods: The synbiotics were administered via syringe, using a special automatic system, into the egg air chamber of Cobb 500 broiler chicks on the 12 thday of egg incubation(2 mg of prebiotics + 105 cfu bacteria per egg).Hatched roosters(total 2,400) were reared on an experimental farm, kept in pens(75 animals per pen), with free access to feed and water. After 42 d animals were slaughtered. Blood serum, pancreas, duodenum and duodenum content were collected.Results: Syn2 increased trypsin activity by 2.5-fold in the pancreas and 1.5-fold in the duodenal content. In the duodenum content, Syn2 resulted in ca 30% elevation in lipase activity and 70% reduction in amylase activity.Syn1 and Syn2 strongly decreased expression of m RNA for GLP-1 and GIP in the duodenum and for GLP-1 receptors in the pancreas. Simultaneously, concentrations of the incretins significantly diminished in the blood serum(P < 0.05). The decreased expression of incretins coincides with changed activity of digestive enzymes in the pancreas and in the duodenal content. The results indicate that incretins are involved in the action of Syn1 and Syn2 or that they may even be their target. No changes were observed in key hormones regulating metabolism(insulin, glucagon, corticosterone, thyroid hormones, and leptin) or in metabolic indices(glucose,NEFA, triglycerides, cholesterol). Additionally, synbiotics did not cause significant changes in the activities of alanine and aspartate aminotransferases in broiler chickens. Simultaneously, the activity of alkaline phosphatase and gamma glutamyl transferase diminished after Syn2 and Syn1, respectively.Conclusion: The selected synbiotics may be used as in ovo additives for broiler chickens, and Syn2 seems to improve their potential digestive proteolytic and lipolytic ability. Our results suggest that synbiotics can be directly or indirectly involved in incretin secretion and reception.
基金supported by the Doctoral Start-Up Foundation of Shanxi Province of China,No. SD1817 (to QQJ)。
文摘Patients with Parkinson's disease(PD) have impaired insulin signaling in the brain. Incretin hormones, including glucagon-like peptide-1(GLP-1) and glucose-dependent insulinotropic polypeptide(GIP), can re-sensitize insulin signaling. In a recent phase II clinical trial, the first GLP-1 mimic, exendin-4, has shown reliable curative effect in patients with PD. DA-CH5 is a novel GLP-1/GIP receptor unimolecular coagonist with a novel peptide sequence added to cross the blood-brain barrier. Here we showed that both exendin-4 and DA-CH5 protected against 6-hydroxydopamine(6-OHDA) cytotoxicity, inhibited apoptosis, improved mitogenesis and induced autophagy flux in SH-SY5Y cells via activation of the insulin receptor substrate-1(IRS-1)/alpha serine/threonine-protein kinase(Akt)/c AMP response element-binding protein(CREB) pathway. We also found that DA-CH5(10 nmol/kg) daily intraperitoneal administration for 30 days post-lesion alleviated motor dysfunction in rats and prevented stereotactic unilateral administration of 6-OHDA induced dopaminergic neurons loss in the substantia nigra pars compacta. However, DA-CH5 showed curative effects in reducing the levels of α-synuclein and the levels of pro-inflammatory cytokines(tumor necrosis factor-α, interleukin-1β). It was also more effective than exendin-4 in inhibiting apoptotic process and protecting mitochondrial functions. In addition, insulin resistance was largely alleviated and the expression of autophagy-related proteins was upregulated in PD model rats after DA-CH5 treatment. These results in this study indicate DA-CH5 plays a therapeutic role in the 6-OHDAunilaterally lesioned PD rat model and is superior to GLP-1 analogue exendin-4. The study was approved by the Animal Ethics Committee of Shanxi Medical University of China.
文摘目的在不同食物负荷情况下,观察阿卡波糖对T2DM患者血清胰升糖素样肽-1(GLP-1)和抑胃肽(GIP)水平的影响。方法新诊断T2DM患者32例,随机分为OGTT组和混合餐试验(MIX)组,使用阿卡波糖片治疗共6周。在服药前1周、第一次服药及治疗6周后行OGTT或MIX,试验时检测0、15、30、60、90、120 min PG、GIP、GLP-1。结果(1)OGTT组与MIX组均随机入组16例,平均年龄分别为(51.7±10.4)、(51.8±11.7)岁。(2)首次使用阿卡波糖治疗,MIX组负荷后PG、GIP均有下降,其中15、30、60、90、120 min PG,15、30、60、90 min GIP,PG、GIP曲线下面积(AUC)比较,差异有统计学意义(P<0.05);MIX组90 min GLP-1较治疗前升高(P<0.05)。OGTT组各点PG、GLP-1、GIP水平及AUC与治疗前比较,差异无统计学意义。(3)治疗6周后,MIX组负荷后PG较治疗前下降,GIP水平随着PG下降,在15、30、60、90 min时较治疗前下降(P<0.05)。MIX组90 min GLP-1较治疗前升高(P<0.05)。OGTT组各点GLP-1、GIP水平及AUC与治疗前比较,差异无统计学意义。结论在不同种类糖负荷下,阿卡波糖对肠促胰岛素的影响可能不同。在复合碳水化合物负荷下,阿卡波糖可能影响GLP-1晚相分泌水平,而GIP可随PG水平的下降而降低。
