Implantation of primary cultured adipocytes that secrete insulin modifies blood glucose levels in diabetic mice
Implantation of primary cultured adipocytes that secrete insulin modifies blood glucose levels in diabetic mice
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DOI：
10.1007/s00125-005-1825-0
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发表时间：
2005-08-01
期刊：
影响因子：
8.2
通讯作者：
Saito, Y
中科院分区：
文献类型：
--
作者：
Ito, M;Bujo, H;Saito, Y
目的/假设：在1型糖尿病患者中，基础胰岛素补充在严格的血糖控制中起核心作用。因此，尽管需要多次注射，安全稳定地补充基础胰岛素是非常可取的。本研究的目的是研究在糖尿病小鼠中使用基因工程、原代培养的脂肪细胞进行补充的程序。方法：利用逆转录病毒载体将可切割的人胰岛素原cDNA转入小鼠原代培养的脂肪细胞。将细胞皮下植入链脲佐菌素诱导的糖尿病小鼠。结果：转染后的细胞在条件培养基中分泌大量成熟胰岛素和c肽。同基因细胞的植入显著改善了高血糖和血液中HbA(1)c的浓度，并以依赖于细胞数量的方式改善，而不引起低血糖。血浆胰岛素浓度依赖于移植细胞数量，循环胰岛素的全身作用通过体重减轻和肝糖原含量的显著改善得到证实。此外，手术切除移植后免疫证实胰岛素分泌的植入物，降低了其降血糖作用，表明必要时可以消除体内表达。结论/解释：这些结果表明，功能化脂肪细胞的自体移植可能会导致糖尿病治疗的临床应用。
Aims/hypothesis: In type 1 diabetic patients, basal insulin supplementation plays a central role in tight glycaemic control. Therefore, safe and steady supplementation of basal insulin is strongly desirable, despite the need for multiple injections. The aim of this study was to investigate a procedure for supplementation using genetically engineered, primary-cultured adipocytes in diabetic mice. Methods: Furin-cleavable human proinsulin cDNA was transferred into murine primary-cultured adipocytes using a retroviral vector. The cells were implanted subcutaneously into streptozotocin-induced diabetic mice. Results: The transfected cells secreted substantial amounts of mature insulin, as well as C-peptide, into conditioned medium. Syngeneic implantation of the cells significantly improved hyperglycaemia and blood HbA(1)c concentrations in a manner that was dependent on cell number, without causing hypoglycaemia. The plasma insulin concentration was dependent on the implanted cell number, and the systemic effect of the circulating insulin was confirmed by marked improvement of body weight reduction and liver glycogen content. Additionally, surgical resection of the implants, in which the insulin secretion was immunologically confirmed after transplantation, diminished the glucose-lowering effect, suggesting that in vivo expression could be eliminated if necessary. Conclusions/interpretations: These results indicate that the autotransplantation of functionalised adipocytes may lead to a clinical application in the treatment of diabetes.