A Small Insulinomimetic Molecule Also Improves Insulin Sensitivity in Diabetic Mice
A Small Insulinomimetic Molecule Also Improves Insulin Sensitivity in Diabetic Mice
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一种小胰岛素模拟分子还可以提高糖尿病小鼠的胰岛素敏感性
作者：
S. Mukherjee;Mrittika Chattopadhyay;Sushmita Bhattacharya;Suman Dasgupta;Sahid Hussain;S. Bharadwaj;Dhrubajyoti Talukdar;Abul Usmani;B. S. Pradhan;S. Majumdar;P. Chattopadhyay;S. Mukhopadhyay;Tushar K Maity;M. Chaudhuri;S. Bhattacharya
糖尿病在地球仪上的急剧增加与胰岛素需求的增加是一致的。这是因为胰腺β细胞的破坏和功能障碍在1型糖尿病和2型糖尿病中都是常见的，胰岛素注射成为一种强迫性行为。由于胰岛素注射剂存在的一些问题，口服活性胰岛素模拟物将是理想的替代品。本文报道了一种小分子过氧钒酸盐化合物DmpzH[VO（O2）2（dmpz）]（以下简称dmp），它与胰岛素受体具有相当大的亲和力（KD-1.17μM），从而激活胰岛素受体酪氨酸激酶及其下游信号分子，导致[14 C] 2脱氧葡萄糖摄取增加。经链脲佐菌素处理的BALB/c小鼠口服dmp可降低血糖水平，并分别显著刺激骨骼肌和脂肪组织对葡萄糖和脂肪酸的摄取。在db/db小鼠中，它通过过量表达PPARγ及其靶基因，即脂联素、CD 36和aP 2，极大地改善了胰岛素敏感性。潜在机制的研究表明，Wnt 3a的过量表达会降低PPARγ的表达，而Wnt 3a基因的dmp抑制会增加PPARγ的表达，从而增加脂联素的表达。由于dmp导致db/db小鼠中脂联素的产生增加，从而降低循环TG和FFA水平，激活骨骼肌中的AMPK，这刺激线粒体生物发生和生物能量学。脂质负荷的降低沿着线粒体活性的增加极大地改善了能量稳态，已经发现这与胰岛素敏感性的增加相关。因此，用dmp获得的结果强烈表明dmp可能是胰岛素替代疗法的潜在候选者。
Dramatic increase of diabetes over the globe is in tandem with the increase in insulin requirement. This is because destruction and dysfunction of pancreatic β-cells are of common occurrence in both Type1 diabetes and Type2 diabetes, and insulin injection becomes a compulsion. Because of several problems associated with insulin injection, orally active insulin mimetic compounds would be ideal substitute. Here we report a small molecule, a peroxyvanadate compound i.e. DmpzH[VO(O2)2(dmpz)], henceforth referred as dmp, which specifically binds to insulin receptor with considerable affinity (KD-1.17μM) thus activating insulin receptor tyrosine kinase and its downstream signaling molecules resulting increased uptake of [14C] 2 Deoxy-glucose. Oral administration of dmp to streptozotocin treated BALB/c mice lowers blood glucose level and markedly stimulates glucose and fatty acid uptake by skeletal muscle and adipose tissue respectively. In db/db mice, it greatly improves insulin sensitivity through excess expression of PPARγ and its target genes i.e. adiponectin, CD36 and aP2. Study on the underlying mechanism demonstrated that excess expression of Wnt3a decreased PPARγ whereas dmp suppression of Wnt3a gene increased PPARγ expression which subsequently augmented adiponectin. Increased production of adiponectin in db/db mice due to dmp effected lowering of circulatory TG and FFA levels, activates AMPK in skeletal muscle and this stimulates mitochondrial biogenesis and bioenergetics. Decrease of lipid load along with increased mitochondrial activity greatly improves energy homeostasis which has been found to be correlated with the increased insulin sensitivity. The results obtained with dmp, therefore, strongly indicate that dmp could be a potential candidate for insulin replacement therapy.
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DOI：
10.1016/s0021-9258(19)40047-1
发表时间：
1990-01
期刊：
The Journal of biological chemistry
影响因子：
--
作者：
P. S. Walker;T. Ramlal;Vivian Sarabia;Ulla Maija Koivisto;P. Bilan;J. Pessin;A. Klip
通讯作者：
P. S. Walker;T. Ramlal;Vivian Sarabia;Ulla Maija Koivisto;P. Bilan;J. Pessin;A. Klip
钒酸钠对脂肪细胞葡萄糖转运的胰岛素样作用是在胰岛素受体后水平介导的。
DOI：
10.1042/bj2380663
发表时间：
1986
期刊：
The Biochemical journal
影响因子：
--
作者：
Green,A
通讯作者：
Green,A
影响因子：
4.6
作者：
D. Crans;Kellie A. Woll;Kestutis Prusinskas;Michael D. Johnson;E. Norkus
通讯作者：
D. Crans;Kellie A. Woll;Kestutis Prusinskas;Michael D. Johnson;E. Norkus
影响因子：
7.7
作者：
Kelley, DE;He, J;Ritov, VB
通讯作者：
Ritov, VB
钒酸盐对大鼠脂肪细胞糖原合酶的胰岛素样作用的新机制。
DOI：
--
发表时间：
1984
期刊：
The Journal of biological chemistry
影响因子：
--
作者：
Tamura,S;Brown,TA;Whipple,JH;Fujita-Yamaguchi,Y;Dubler,RE;Cheng,K;Larner,J
通讯作者：
Larner,J