Pôle de Chirurgie Expérimentale et Transplantation, Laboratory of Experimental Surgery, Université Catholique de Louvain, Secteur des Sciences de la Santé, Brussels, Belgium.
Cell Transplant. 2013;22(11):2161-73. doi: 10.3727/096368912X657864. Epub 2012 Oct 8.
Pig islets demonstrate significantly lower insulin secretion after glucose stimulation than human islets (stimulation index of ∼12 vs. 2 for glucose 1 and 15 mM, respectively) due to a major difference in β- and α-cell composition in islets (60% and 25% in humans and 90% and 8% in pigs, respectively). This leads to a lower rise in 3',5'-cyclic adenosine monophosphate (cAMP) in pig β-cells. Since glucagon is the major hormonal effector of cAMP in β-cells, we modified pig islet structure in vivo to increase the proportion of α-cells per islet and to improve insulin secretion. Selected doses (0, 30, 50, 75, and 100 mg/kg) of streptozotocin (STZ) were intravenously injected in 32 young pigs to assess pancreatic (insulin and glucagon) hormone levels, islet remodeling (histomorphometry for α- and β-cell proportions), and insulin and glucagon secretion in isolated islets. Endocrine structure and hormonal content of pig islets were compared with those of human islets. The dose of STZ was significantly correlated with reductions in pancreatic insulin content (p< 0.05, r(2) = 0.77) and the proportion of β-cells (p < 0.05, r(2) = 0.88). A maximum of 50 mg/kg STZ was required for optimal structure remodeling, with an increased proportion of α-cells per islet (26% vs. 48% α-cells per islet for STZ <50 mg/kg vs. >75 mg/kg; p < 0.05) without β-cell dysfunction. Three months after STZ treatment (30/50 mg/kg STZ), pig islets were isolated and compared with isolated control islets (0 mg/kg STZ). Isolated islets from STZ-treated (30/50 mg/kg) pigs had a higher proportion of α-cells than those from control animals (32.0% vs. 9.6%, respectively, p < 0.05). After in vitro stimulation, isolated islets from STZ-treated pigs demonstrated significantly higher glucagon content (65.4 vs. 21.0 ng/ml, p < 0.05) and insulin release (144 µU/ml) than nontreated islets (59 µU/ml, p < 0.05), respectively. Low-dose STZ (<50 mg/kg) can modify the structure of pig islets in vivo and improve insulin secretion after isolation.
猪胰岛在葡萄糖刺激后显示出明显低于人胰岛的胰岛素分泌（刺激指数分别约为 12 和 2 对于葡萄糖 1 和 15mM），这是由于胰岛中β-和α-细胞组成的主要差异（分别为 60%和 25%在人类和 90%和 8%在猪中）。这导致猪β-细胞中 3'，5'-环腺苷单磷酸（cAMP）的升高较低。由于胰高血糖素是β-细胞中 cAMP 的主要激素效应物，我们在体内修饰了猪胰岛结构，以增加胰岛内α-细胞的比例并改善胰岛素分泌。在 32 只幼猪中静脉注射不同剂量（0、30、50、75 和 100mg/kg）链脲佐菌素（STZ），以评估胰腺（胰岛素和胰高血糖素）激素水平、胰岛重塑（α-和β-细胞比例的组织形态计量学）以及分离胰岛中的胰岛素和胰高血糖素分泌。猪胰岛的内分泌结构和激素含量与人类胰岛进行了比较。STZ 剂量与胰腺胰岛素含量的降低呈显著相关（p<0.05，r(2) = 0.77）和β-细胞比例（p<0.05，r(2) = 0.88）。最高 50mg/kg 的 STZ 即可达到最佳结构重塑，每个胰岛的α-细胞比例增加（50mg/kg STZ < 50mg/kg 与 >75mg/kg STZ 相比，每个胰岛的α-细胞比例分别为 26%和 48%；p<0.05），而β-细胞功能不受影响。STZ 治疗 3 个月后（30/50mg/kg STZ），分离猪胰岛并与对照分离胰岛（0mg/kg STZ）进行比较。与对照动物相比，来自 STZ 处理（30/50mg/kg）猪的胰岛的α-细胞比例更高（分别为 32.0%和 9.6%，p<0.05）。在体外刺激后，来自 STZ 处理猪的胰岛的胰高血糖素含量（65.4ng/ml）和胰岛素释放（144µU/ml）明显高于未经处理的胰岛（分别为 59µU/ml，p<0.05）。低剂量 STZ（<50mg/kg）可在体内修饰猪胰岛的结构，并改善分离后胰岛素的分泌。
