Sustained expression of GLP-1 receptor differentially modulates β-cell functions in diabetic and nondiabetic mice.
Sustained expression of GLP-1 receptor differentially modulates β-cell functions in diabetic and nondiabetic mice.
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DOI：
10.1016/j.bbrc.2016.01.177
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发表时间：
2016-02-26
影响因子：
3.1
通讯作者：
Shimomura I
中科院分区：
文献类型：
--
作者：
Kubo F;Miyatsuka T;Sasaki S;Takahara M;Yamamoto Y;Shimo N;Watada H;Kaneto H;Gannon M;Matsuoka TA;Shimomura I
胰升糖素样肽1(GLP-1)在维持β细胞功能方面发挥重要作用，如胰岛素分泌和增殖。虽然GLP-1受体(GLP1R)的表达水平在糖尿病啮齿动物的胰岛中受到影响，但在糖尿病进展过程中，GLP1R mRNA水平何时以及在多大程度上降低仍不清楚。在本研究中，我们对不同年龄的db/db糖尿病小鼠的胰岛进行了实时荧光定量聚合酶链式反应，发现GLP1R的表达水平在4周龄时与非糖尿病db/db对照组相当，在8周龄和12周龄时显著降低。为了研究GLP1R的恢复表达是否会影响糖尿病的表型，我们建立了转基因小鼠模型Pdx1PB-Creer™；CAG-CAT-GLP1R(βGLP1R)，该模型允许在β细胞中特异性地诱导GLP1R的表达。而外源性GLP1R的表达对非糖尿病βGLP1R、βGLP1R、db/db小鼠的糖耐量无明显影响；在葡萄糖负荷试验中，db/db小鼠表现出较高的血糖和较低的胰岛素水平。相比之下，四周的Exendin-4治疗改善了βGLP1R；db/db小鼠的血糖水平，并增加了血清胰岛素水平，显著高于对照组db/db小鼠。外源性GLP1R在非糖尿病和糖尿病小鼠中的这些不同作用表明，在糖尿病条件下，可能需要下调GLP1R来减缓β细胞衰竭的进展。
Glucagon-like peptide 1 (GLP-1) has been shown to play important roles in maintaining β-cell functions, such as insulin secretion and proliferation. While expression levels of GLP-1 receptor (Glp1r) are compromised in the islets of diabetic rodents, it remains unclear when and to what degree Glp1r mRNA levels are decreased during the progression of diabetes. In this study, we performed real-time PCR with the islets of db/db diabetic mice at different ages, and found that the expression levels of Glp1r were comparable to those of the islets of nondiabetic db/misty controls at the age of four weeks, and were significantly decreased at the age of eight and 12 weeks. To investigate whether restored expression of Glp1r affects the diabetic phenotypes, we generated the transgenic mouse model Pdx1PB-CreER™; CAG-CAT-Glp1r (βGlp1r) that allows for induction of Glp1r expression specifically in β cells. Whereas the expression of exogenous Glp1r had no measurable effect on glucose tolerance in nondiabetic βGlp1r;db/misty mice, βGlp1r;db/db mice exhibited higher glucose and lower insulin levels in blood on glucose challenge test than control db/db littermates. In contrast, four weeks of treatment with exendin-4 improved the glucose profiles and increased serum insulin levels in βGlp1r;db/db mice, to significantly higher levels than those in control db/db mice. These differential effects of exogenous Glp1r in nondiabetic and diabetic mice suggest that downregulation of Glp1r might be required to slow the progression of β-cell failure under diabetic conditions.