Our previous investigation found that exendin-4 （Ex-4） , a peptide analogue of glucagon-like peptide 1 （GLP-1） , induced bone formation probably by osteoblast activation. Nevertheless, previous investigations did ...Our previous investigation found that exendin-4 （Ex-4） , a peptide analogue of glucagon-like peptide 1 （GLP-1） , induced bone formation probably by osteoblast activation. Nevertheless, previous investigations did not observe any expression of GLP-1 receptors in osteoblasts, indicating that the direct cell target of GLP-1 and its ana- logues might not be osteoblasts but some other types of cells yet to be identified. To elucidate the underlying mecha- nisms, we performed further investigation in the present study and found that GLP-1 receptor was only identified in bone marrow mesenchymal stem cells （BMSCs）. Furthermore, activation of GLP-1 receptor by Ex-4 promoted the differentiation of B MSCs into osteoblast, which was associated with activation of PKA, nuclear translocation of [5- catenin, activation of PI3K/AKT and inhibition of GSK3β. Ex-4 also inhibited the adipocyte differentiation of BM- SCs, as evidenced by inhibition of PPARγ, lipoprotein lipase expression and lipid production. Blockade of GLP-1 receptor, PKA, PI3K or Wnt pathway, or respective knock-down of GLP-1 receptor and β-catenin in BMSCs inhib- ited the Ex-4 mediated effects. The results indicated that the GLP-1 receptor mediated osteoblastic differentiation and bone formation through stimulation of PKA/β-catenin signaling and inhibition of PKA/PI3IC/AKT/GSK3β？ signaling pathway in BMSCs. The findings reveal a new role of GLP-1 receptor for regulating osteoblastic differentia- tion of B MSCs and may provide a molecular basis for novel anabolic therapeutics against osteoporosis.展开更多
美国糖尿病协会(American Diabetes Association,ADA)和欧洲糖尿病研究协会(European Association for the Study of Diabetes,EASD)刚刚发布了更新版的《2018年2型糖尿病高血糖管理共识声明》(以下简称"新共识"),概述了2型...美国糖尿病协会(American Diabetes Association,ADA)和欧洲糖尿病研究协会(European Association for the Study of Diabetes,EASD)刚刚发布了更新版的《2018年2型糖尿病高血糖管理共识声明》(以下简称"新共识"),概述了2型糖尿病高血糖的管理,更新了以患者为中心的决策和支持,提出在制订降糖方案时应综合考虑2型糖尿病患者心血管与慢性肾脏病等合并症的新理念。同时,新共识也提出了关于钠-葡萄糖协同转运蛋白2抑制剂与胰高血糖素样肽-1受体激动剂的新挑战。展开更多
文摘Our previous investigation found that exendin-4 （Ex-4） , a peptide analogue of glucagon-like peptide 1 （GLP-1） , induced bone formation probably by osteoblast activation. Nevertheless, previous investigations did not observe any expression of GLP-1 receptors in osteoblasts, indicating that the direct cell target of GLP-1 and its ana- logues might not be osteoblasts but some other types of cells yet to be identified. To elucidate the underlying mecha- nisms, we performed further investigation in the present study and found that GLP-1 receptor was only identified in bone marrow mesenchymal stem cells （BMSCs）. Furthermore, activation of GLP-1 receptor by Ex-4 promoted the differentiation of B MSCs into osteoblast, which was associated with activation of PKA, nuclear translocation of [5- catenin, activation of PI3K/AKT and inhibition of GSK3β. Ex-4 also inhibited the adipocyte differentiation of BM- SCs, as evidenced by inhibition of PPARγ, lipoprotein lipase expression and lipid production. Blockade of GLP-1 receptor, PKA, PI3K or Wnt pathway, or respective knock-down of GLP-1 receptor and β-catenin in BMSCs inhib- ited the Ex-4 mediated effects. The results indicated that the GLP-1 receptor mediated osteoblastic differentiation and bone formation through stimulation of PKA/β-catenin signaling and inhibition of PKA/PI3IC/AKT/GSK3β？ signaling pathway in BMSCs. The findings reveal a new role of GLP-1 receptor for regulating osteoblastic differentia- tion of B MSCs and may provide a molecular basis for novel anabolic therapeutics against osteoporosis.
文摘目的:阐明锌-α2-糖蛋白(Zinc-α2-glycoprotein,ZAG)与胰岛素抵抗的关系以及胰升糖素样肽1(glucagon-like peptide-1,GLP-1)受体激动剂治疗的影响。方法:新发2型糖尿病(newly diagnosed T2DM,n T2DM)患者120例随机分为利拉鲁肽组(n=45,利拉鲁肽0.6~1.8 mg,i H qd)、利拉鲁肽+二甲双胍组(n=45,利拉鲁肽0.6~1.8 mg,i H qd+二甲双胍0.5g bid)、安慰剂组(n=30,生理盐水150μl i H qd+二甲双胍0.5g bid),治疗12周,同期选取年龄、性别相匹配的健康体检者作为健康对照组(n=30)。治疗前后分别行75g OGTT、胰岛素钳夹试验并检测血浆ZAG、脂联素(adiponectin,ADI)水平及相关代谢指标。结果:n T2DM患者基础血浆ZAG水平明显低于健康对照组(P<0.01),通过利拉鲁肽、利拉鲁肽+二甲双胍治疗后12周,患者的糖化血红蛋白,空腹血糖,糖负荷后2 h血糖,甘油三酯和稳态模型评估胰岛素抵抗指数均较治疗前明显下降(P<0.05),通过安慰剂治疗后上述指标明显高于利拉鲁肽治疗组(P<0.05);而在钳夹过程中,M值明显升高(P<0.01)。此外,与治疗前相比,利拉鲁肽治疗后血浆ZAG、ADI水平明显增加(P<0.01)。结论:n T2DM患者经GLP-1受体激动剂治疗后,糖代谢及胰岛素敏感性得到明显改善,血浆ZAG水平也明显升高,提示ZAG将可能被作为代谢综合征或者T2DM的一个新的生物标志物。
文摘美国糖尿病协会(American Diabetes Association,ADA)和欧洲糖尿病研究协会(European Association for the Study of Diabetes,EASD)刚刚发布了更新版的《2018年2型糖尿病高血糖管理共识声明》(以下简称"新共识"),概述了2型糖尿病高血糖的管理,更新了以患者为中心的决策和支持,提出在制订降糖方案时应综合考虑2型糖尿病患者心血管与慢性肾脏病等合并症的新理念。同时,新共识也提出了关于钠-葡萄糖协同转运蛋白2抑制剂与胰高血糖素样肽-1受体激动剂的新挑战。
