Pioglitazone Reverses Markers of Islet Beta-Cell De-Differentiation in db/db Mice While Modulating Expression of Genes Controlling Inflammation and Browning in White Adipose Tissue from Insulin-Resistant Mice and Humans.
Pioglitazone Reverses Markers of Islet Beta-Cell De-Differentiation in db/db Mice While Modulating Expression of Genes Controlling Inflammation and Browning in White Adipose Tissue from Insulin-Resistant Mice and Humans.
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DOI：
10.3390/biomedicines9091189
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发表时间：
2021-09-10
期刊：
影响因子：
4.7
通讯作者：
Burke SJ
中科院分区：
文献类型：
--
作者：
Collier JJ;Batdorf HM;Merrifield KL;Martin TM;White U;Ravussin E;Burk DH;Cooley CR;Karlstad MD;Burke SJ
肥胖、胰岛素抵抗和2型糖尿病会增加人类的发病率和死亡率。db/db小鼠是一种重要的小鼠模型，它显示了人类疾病的许多关键特征。在此，我们使用吡格列酮（一种具有胰岛素增敏特性的噻唑烷二酮）来研究血糖水平、胰岛β细胞健康和成熟指标以及脂肪组织中的基因表达。口服吡格列酮降低了db/db小鼠的血糖水平，并相应增加了呼吸商，这表明全身碳水化合物利用得到改善。此外，使用吡格列酮处理的db/db小鼠和人的白色脂肪组织显示甘油激酶的表达增加。服用吡格列酮的db/db小鼠和人都显示出UCP-1的表达增加，UCP-1是一种典型的与棕色脂肪组织相关的标志物。此外，经吡格列酮处理的db/db小鼠胰腺β-细胞中胰岛素和Nkx6.1的表达增加，去分化标志物Aldh1a3的丰度降低。总的来说，这些发现表明四周的吡格列酮治疗改善了db/db小鼠的整体代谢健康。我们的数据与已发表的使用吡格列酮的人类受试者的报告以及使用吡格列酮治疗的受试者的人类脂肪组织分析一致。总之，目前的研究提供了吡格列酮恢复代谢健康关键标志物的证据，也展示了db/db小鼠在理解与人类代谢疾病相关的机制和提供治疗益处的干预措施方面的效用。
Obesity, insulin resistance, and type 2 diabetes contribute to increased morbidity and mortality in humans. The db/db mouse is an important mouse model that displays many key features of the human disease. Herein, we used the drug pioglitazone, a thiazolidinedione with insulin-sensitizing properties, to investigate blood glucose levels, indicators of islet β-cell health and maturity, and gene expression in adipose tissue. Oral administration of pioglitazone lowered blood glucose levels in db/db mice with a corresponding increase in respiratory quotient, which indicates improved whole-body carbohydrate utilization. In addition, white adipose tissue from db/db mice and from humans treated with pioglitazone showed increased expression of glycerol kinase. Both db/db mice and humans given pioglitazone displayed increased expression of UCP-1, a marker typically associated with brown adipose tissue. Moreover, pancreatic β-cells from db/db mice treated with pioglitazone had greater expression of insulin and Nkx6.1 as well as reduced abundance of the de-differentiation marker Aldh1a3. Collectively, these findings indicate that four weeks of pioglitazone therapy improved overall metabolic health in db/db mice. Our data are consistent with published reports of human subjects administered pioglitazone and with analysis of human adipose tissue taken from subjects treated with pioglitazone. In conclusion, the current study provides evidence that pioglitazone restores key markers of metabolic health and also showcases the utility of the db/db mouse to understand mechanisms associated with human metabolic disease and interventions that provide therapeutic benefit.
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影响因子：
8.1
作者：
Burke SJ;Batdorf HM;Burk DH;Martin TM;Mendoza T;Stadler K;Alami W;Karlstad MD;Robson MJ;Blakely RD;Mynatt RL;Collier JJ
通讯作者：
Collier JJ
影响因子：
7.7
作者：
Defronzo RA;Tripathy D;Schwenke DC;Banerji M;Bray GA;Buchanan TA;Clement SC;Gastaldelli A;Henry RR;Kitabchi AE;Mudaliar S;Ratner RE;Stentz FB;Musi N;Reaven PD;ACT NOW Study
通讯作者：
ACT NOW Study
影响因子：
7.7
作者：
Ishida E;Kim-Muller JY;Accili D
通讯作者：
Accili D
影响因子：
2.4
作者：
DeFronzo, Ralph A.;Inzucchi, Silvio;Nissen, Steven E.
通讯作者：
Nissen, Steven E.
影响因子：
2.9
作者：
Croasdell A;Duffney PF;Kim N;Lacy SH;Sime PJ;Phipps RP
通讯作者：
Phipps RP