Montréal Diabetes Research Center, CRCHUM, University of Montreal, QC, Canada.
Diabetes Res Clin Pract. 2010 Mar;87(3):322-8. doi: 10.1016/j.diabres.2009.12.020. Epub 2010 Jan 25.
Prolonged exposure of pancreatic beta-cells to elevated levels of glucose and fatty acids adversely affects insulin secretion and gene expression.
To examine whether the GLP-1 agonist exenatide or the inhibitor of the GLP-1-degrading enzyme dipeptidyl peptidase 4 (DPP-4) sitagliptin rescue insulin gene expression in rats infused for 72h with glucose+Intralipid, independently from their glucose-lowering action.
Wistar rats were infused alternatively with glucose or Intralipid for cycles of 4h each for a total of 72h. The animals received exenatide (5microg/kg/day IV) or sitagliptin (5mg/kg/day IV) continuously starting 4 days prior to and continuing throughout the 3-day infusion period.
Plasma glucose, fatty acids, insulin and C-peptide levels were unaffected by exenatide or sitagliptin treatment during the infusion period. Insulin mRNA levels increased in response to the glucose infusion, but this increase was abolished in islets from rats receiving glucose+Intralipid. Neither exenatide nor sitagliptin administration rescued insulin mRNA in glucose+Intralipid infused rats.
Neither a GLP-1 agonist nor a DPP-4 inhibitor, at doses that do not alter blood glucose levels, prevented the inhibition of insulin gene expression in this in vivo model of glucolipotoxicity.
胰腺β细胞长期暴露于高浓度葡萄糖和脂肪酸中会对胰岛素分泌和基因表达产生不利影响。
研究 GLP-1 激动剂 exenatide 或 GLP-1 降解酶二肽基肽酶 4（DPP-4）抑制剂 sitagliptin 是否能够独立于其降血糖作用，挽救在输注葡萄糖+Intralipid 72 小时的大鼠中胰岛素基因的表达。
Wistar 大鼠交替输注葡萄糖或 Intralipid，每 4 小时为一个周期，总共持续 72 小时。动物在开始前 4 天并在整个 3 天输注期间持续接受 exenatide（5μg/kg/天 IV）或 sitagliptin（5mg/kg/天 IV）治疗。
在输注期间，exenatide 或 sitagliptin 治疗对血浆葡萄糖、脂肪酸、胰岛素和 C 肽水平没有影响。胰岛素 mRNA 水平在葡萄糖输注时增加，但在接受葡萄糖+Intralipid 输注的大鼠胰岛中，这种增加被消除。exenatide 或 sitagliptin 给药均不能挽救葡萄糖+Intralipid 输注大鼠的胰岛素 mRNA。
在不改变血糖水平的剂量下，既没有 GLP-1 激动剂，也没有 DPP-4 抑制剂，能够防止这种在体内糖脂毒性模型中胰岛素基因表达的抑制。
