TXNIP regulates peripheral glucose metabolism in humans.
TXNIP regulates peripheral glucose metabolism in humans.
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TXNIP调节人类的外周葡萄糖代谢。
DOI：
10.1371/journal.pmed.0040158
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发表时间：
2007-05
期刊：
影响因子：
15.8
通讯作者：
Mootha, Vamsi K.
中科院分区：
文献类型：
--
作者：
Parikh, Hemang;Carlsson, Emma;Chutkow, William A.;Johansson, Lovisa E.;Storgaard, Heidi;Poulsen, Pernille;Saxena, Richa;Ladd, Christine;Schulze, P. Christian;Mazzini, Michael J.;Jensen, Christine Bjorn;Krook, Anna;Bjornholm, Marie;Tornqvist, Hans;Zierath, Juleen R.;Ridderstrale, Martin;Altshuler, David;Lee, Richard T.;Vaag, Allan;Groop, Leif C.;Mootha, Vamsi K.
2型糖尿病（T2DM）以胰岛素分泌和作用缺陷为特征。骨骼肌葡萄糖摄取受损被认为是T2DM自然历史上最早的特征之一，尽管其潜在机制尚不清楚。我们将人类胰岛素/葡萄糖钳生理研究与全基因组表达谱相结合，确定硫氧还蛋白相互作用蛋白（TXNIP）是胰岛素强烈抑制而葡萄糖刺激表达的基因。在健康个体中，其表达与全身葡萄糖摄取呈负相关。在培养的脂肪细胞中强制表达TXNIP可显著降低葡萄糖摄取，而在脂肪细胞和骨骼肌中通过RNA干扰沉默可增强葡萄糖摄取，证实该基因产物也是葡萄糖摄取的调节因子。TXNIP的表达在糖尿病前期和糖尿病患者的肌肉中持续升高，尽管在4450个斯堪的纳维亚个体的小组中，我们没有发现TXNIP基因的共同遗传变异与T2DM之间的关联。TXNIP调节人类骨骼肌中胰岛素依赖性和胰岛素非依赖性的葡萄糖摄取途径。结合最近的研究表明TXNIP与胰腺β细胞葡萄糖毒性有关，我们的数据表明TXNIP可能在显性T2DM前的葡萄糖稳态缺陷中发挥关键作用。Vamsi Mootha， Leif Groop及其同事报告说，TXNIP调节人类骨骼肌中胰岛素依赖和独立的葡萄糖摄取途径，并且其表达在糖尿病前期和2型糖尿病患者中升高。糖尿病的流行正威胁着世界的健康。2.46亿人（占世界人口的6%）已经患有糖尿病，据估计，在20年内，将有3.8亿人患有这种慢性疾病，其中大多数在发展中国家。糖尿病的特点是高血糖（葡萄糖）水平。当胰腺不能产生足够的胰岛素（1型糖尿病）或当身体对胰岛素反应不良（2型糖尿病）时，它就会出现。胰岛素是对高血糖水平的反应，它指示肌肉、脂肪和肝细胞从血液中吸收葡萄糖（食物消化的产物）；细胞使用葡萄糖作为燃料。2型糖尿病占所有糖尿病病例的90%，其特点是靶组织对胰岛素的葡萄糖摄取受损（这种“胰岛素抵抗”是2型糖尿病的最初迹象之一）和肝细胞不适当的葡萄糖释放。随着时间的推移，胰腺分泌的胰岛素也会减少。这些变化导致葡萄糖稳态不佳（血糖水平控制不足），这可能导致危及生命的并发症，如肾衰竭和心脏病发作。如果要阻止全球糖尿病的流行，研究人员需要更好地了解葡萄糖稳态，需要确定这个复杂控制系统的哪些部分在2型糖尿病中出错。这一信息可能会提出预防2型糖尿病发展的方法，并可能揭示减缓或逆转疾病进程的药物靶点。在这项研究中，研究人员使用了多种方法来确定一种新的葡萄糖稳态介质，并研究这种介质是否与2型糖尿病的发展有因果关系。研究人员在提高血液胰岛素水平之前和之后，从没有患糖尿病的人身上提取了小块肌肉样本，并使用一种称为“微阵列表达谱”的技术来识别胰岛素诱导或抑制表达的基因。后一种基因是硫氧还蛋白相互作用蛋白（TXNIP），该基因的表达受葡萄糖强烈诱导，但受胰岛素抑制。接下来，他们使用先前发表的微阵列表达数据显示，TXNIP在糖尿病或糖尿病前期（血糖水平轻微升高的一种情况）患者肌肉中的表达始终高于正常人。然后，研究人员再次使用先前发表的数据，检查TXNIP的表达是否与葡萄糖摄取相关。在非糖尿病患者和糖尿病前期患者中，随着葡萄糖摄取率的增加，TXNIP的表达降低，但在糖尿病患者中没有这种负相关。最后，通过控制实验室培养的胰岛素反应细胞中的TXNIP表达水平，研究人员发现TXNIP过表达减少了基础和胰岛素刺激的葡萄糖摄取，但减少TXNIP表达具有相反的效果。这些结果提供了强有力的证据，证明TXNIP是人体内葡萄糖稳态的调节剂。具体来说，研究人员提出TXNIP通过作为葡萄糖和胰岛素敏感开关来调节人体外周的葡萄糖摄取。他们还提出了它是如何参与2型糖尿病的发展的。在疾病早期，少量胰岛素缺乏或血糖水平轻微升高会增加肌肉中TXNIP的表达，抑制这些细胞对葡萄糖的摄取。最初，胰腺会通过产生更多的胰岛素来补偿这一点，但这种补偿最终会失败，导致血糖水平上升到足以增加胰腺中TXNIP的表达。先前发表的研究结果表明，这将诱导胰腺中产生胰岛素的细胞的损失，从而进一步减少周围细胞的胰岛素产生和葡萄糖摄取，最终导致2型糖尿病。虽然关于TXNIP在葡萄糖稳态中的确切作用还有许多未解之谜，但这些结果有助于解释糖尿病发展早期发生的许多葡萄糖控制变化。此外，他们认为，旨在调节TXNIP活性的干预措施可能会打破最终导致2型糖尿病的恶性循环。请通过本摘要的在线版本http://dx.doi.org/10.1371/journal.pmed.0040158访问这些网站。MedlinePlus百科全书有关于糖尿病的页面，美国国家糖尿病、消化和肾脏疾病研究所有关于糖尿病患者的信息，美国疾病控制和预防中心的患者和专业人员可以获得关于糖尿病的信息，美国糖尿病协会为患者提供关于糖尿病的信息，国际糖尿病联合会有关于糖尿病的信息和最近关于全球糖尿病流行的新闻稿
Type 2 diabetes mellitus (T2DM) is characterized by defects in insulin secretion and action. Impaired glucose uptake in skeletal muscle is believed to be one of the earliest features in the natural history of T2DM, although underlying mechanisms remain obscure. We combined human insulin/glucose clamp physiological studies with genome-wide expression profiling to identify thioredoxin interacting protein (TXNIP) as a gene whose expression is powerfully suppressed by insulin yet stimulated by glucose. In healthy individuals, its expression was inversely correlated to total body measures of glucose uptake. Forced expression of TXNIP in cultured adipocytes significantly reduced glucose uptake, while silencing with RNA interference in adipocytes and in skeletal muscle enhanced glucose uptake, confirming that the gene product is also a regulator of glucose uptake. TXNIP expression is consistently elevated in the muscle of prediabetics and diabetics, although in a panel of 4,450 Scandinavian individuals, we found no evidence for association between common genetic variation in the TXNIP gene and T2DM. TXNIP regulates both insulin-dependent and insulin-independent pathways of glucose uptake in human skeletal muscle. Combined with recent studies that have implicated TXNIP in pancreatic β-cell glucose toxicity, our data suggest that TXNIP might play a key role in defective glucose homeostasis preceding overt T2DM. Vamsi Mootha, Leif Groop, and colleagues report that TXNIP regulates insulin-dependent and -independent pathways of glucose uptake in human skeletal muscle and that its expression is elevated in individuals with prediabetes and type 2 diabetes. An epidemic of diabetes mellitus is threatening world health. 246 million people (6% of the world's population) already have diabetes and it is estimated that within 20 years, 380 million people will have this chronic disease, most of them in developing countries. Diabetes is characterized by high blood sugar (glucose) levels. It arises when the pancreas does not make enough insulin (type 1 diabetes) or when the body responds poorly to insulin (type 2 diabetes). Insulin, which is released in response to high blood glucose levels, instructs muscle, fat, and liver cells to take glucose (a product of food digestion) out of the bloodstream; cells use glucose as a fuel. Type 2 diabetes, which accounts for 90% of all cases of diabetes, is characterized by impaired glucose uptake by target tissues in response to insulin (this “insulin resistance” is one of the first signs of type 2 diabetes) and inappropriate glucose release from liver cells. Over time, the pancreas may also make less insulin. These changes result in poor glucose homeostasis (inadequate control of blood sugar levels), which can cause life-threatening complications such as kidney failure and heart attacks. If the world diabetes epidemic is to be halted, researchers need a better understanding of glucose homeostasis and need to identify which parts of this complex control system go awry in type 2 diabetes. This information might suggest ways to prevent type 2 diabetes developing in the first place and might reveal targets for drugs that could slow or reverse the disease process. In this study, the researchers have used multiple approaches to identify a new mediator of glucose homeostasis and to investigate whether this mediator is causally involved in the development of type 2 diabetes. The researchers took small muscle samples from people who did not have diabetes before and after increasing their blood insulin levels and used a technique called “microarray expression profiling” to identify genes whose expression was induced or suppressed by insulin. One of the latter genes was thioredoxin interacting protein (TXNIP), a gene whose expression is strongly induced by glucose yet suppressed by insulin. They next used previously published microarray expression data to show that TXNIP expression was consistently higher in the muscles of patients with diabetes or prediabetes (a condition in which blood glucose levels are slightly raised) than in normal individuals. The researchers then examined whether TXNIP expression was correlated with glucose uptake, again using previously published data. In people with no diabetes and those with prediabetes, as glucose uptake rates increased, TXNIP expression decreased but this inverse correlation was missing in people with diabetes. Finally, by manipulating TXNIP expression levels in insulin-responsive cells grown in the laboratory, the researchers found that TXNIP overexpression reduced basal and insulin-stimulated glucose uptake but that reduced TXNIP expression had the opposite effect. These results provide strong evidence that TXNIP is a regulator of glucose homeostasis in people. Specifically, the researchers propose that TXNIP regulates glucose uptake in the periphery of the human body by acting as a glucose- and insulin-sensitive switch. They also suggest how it might be involved in the development of type 2 diabetes. Early in the disease process, a small insulin deficiency or slightly raised blood sugar levels would increase TXNIP expression in muscles and suppress glucose uptake by these cells. Initially, the pancreas would compensate for this by producing more insulin, but this compensation would eventually fail, allowing blood sugar levels to rise sufficiently to increase TXNIP expression in the pancreas. Previously published results suggest that this would induce the loss of insulin-producing cells in the pancreas, thus further reducing insulin production and glucose uptake in the periphery and, ultimately, resulting in type 2 diabetes. Although there are many unanswered questions about the exact role of TXNIP in glucose homeostasis, these results help to explain many of the changes in glucose control that occur early in the development of diabetes. Furthermore, they suggest that interventions designed to modulate the activity of TXNIP might break the vicious cycle that eventually leads to type 2 diabetes. Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.0040158. The MedlinePlus encyclopedia has pages on diabetes The US National Institute of Diabetes and Digestive and Kidney Diseases has information for patients on diabetes Information on diabetes is available for patients and professionals from the US Centers for Disease Control and Prevention The American Diabetes Association provides information on diabetes for patients International Diabetes Federation has information on diabetes and a recent press release on the global diabetes epidemic
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通过当前调用过滤对微阵列实验分析的影响。
影响因子：
3
作者：
McClintick, JN;Edenberg, HJ
通讯作者：
Edenberg, HJ
DOI：
10.1016/s0006-291x(03)01124-0
发表时间：
2003-07-18
影响因子：
3.1
作者：
Al-Khalili, L;Cartee, GD;Krook, A
通讯作者：
Krook, A
影响因子：
4.2
作者：
Donnelly, KL;Margosian, MR;Parks, EJ
通讯作者：
Parks, EJ
影响因子：
56.9
作者：
Golub, TR;Slonim, DK;Lander, ES
通讯作者：
Lander, ES
影响因子：
30.8
作者：
de Bakker, PIW;Yelensky, R;Altshuler, D
通讯作者：
Altshuler, D