Moullé Valentine S, Vivot Kevin, Tremblay Caroline, Zarrouki Bader, Ghislain Julien, Poitout Vincent
Montreal Diabetes Research Center, University of Montreal, Montreal, QC, Canada.
The University of Montreal Hospital Research Centre (CRCHUM), 900 Saint-Denis, Montreal, QC, H2X 0A9, Canada.
Diabetologia. 2017 May;60(5):879-888. doi: 10.1007/s00125-016-4197-8. Epub 2017 Jan 11.
AIMS/HYPOTHESIS: The mechanisms underlying pancreatic islet mass expansion have attracted considerable interest as potential therapeutic targets to prevent or delay the onset of type 2 diabetes. While several factors promoting beta cell proliferation have been identified, in the context of nutrient excess the roles of glucose or NEFA in relation to insulin resistance remain unclear. Here we tested the hypothesis that glucose and NEFA synergistically and reversibly promote beta cell proliferation in the context of nutrient-induced insulin resistance.
Using 72 h infusions of glucose (GLU) or the oleate-enriched lipid emulsion ClinOleic (CLI), singly or in combination, we assessed beta cell proliferation, islet mass and insulin sensitivity in male Lewis rats. The effects of nutrients and endogenous circulating factors were examined in isolated and transplanted islets. Reversibility was studied 3 and 6 days after the end of the infusion.
GLU infusions modestly stimulated beta cell proliferation, CLI alone had no effect and GLU+CLI infusions markedly stimulated beta cell proliferation. Insulin sensitivity was equally decreased in GLU and GLU+CLI infusions. GLU+CLI infusions also stimulated beta cell proliferation in islets transplanted under the kidney capsule, albeit to a lesser extent compared with endogenous islets. Ex vivo, the combination of glucose and NEFA enhanced beta cell proliferation in rat and human islets independently from secreted insulin, and serum from GLU+CLI-infused rats potentiated the effect of glucose. Glucose tolerance, beta cell proliferation and islet mass were all restored to normal levels 6 days after termination of the infusion.
CONCLUSIONS/INTERPRETATION: Glucose and NEFA synergistically and reversibly promote beta cell proliferation in part via direct action on the beta cell and independently from secreted insulin.
目的/假设：胰岛体积增大的潜在机制作为预防或延缓2型糖尿病发病的潜在治疗靶点，已引起了广泛关注。虽然已经确定了几种促进β细胞增殖的因素，但在营养过剩的情况下，葡萄糖或非酯化脂肪酸（NEFA）与胰岛素抵抗的关系仍不清楚。在此，我们验证了以下假设：在营养诱导的胰岛素抵抗情况下，葡萄糖和NEFA协同且可逆地促进β细胞增殖。
通过对雄性Lewis大鼠单独或联合输注葡萄糖（GLU）或富含油酸的脂质乳剂ClinOleic（CLI）72小时，我们评估了β细胞增殖、胰岛体积和胰岛素敏感性。在分离和移植的胰岛中研究了营养物质和内源性循环因子的作用。在输注结束后3天和6天研究了可逆性。
输注GLU适度刺激β细胞增殖，单独输注CLI无作用，而输注GLU+CLI显著刺激β细胞增殖。输注GLU和GLU+CLI时胰岛素敏感性均同样降低。输注GLU+CLI也刺激了肾被膜下移植胰岛的β细胞增殖，尽管与内源性胰岛相比程度较小。在体外，葡萄糖和NEFA的组合独立于分泌的胰岛素增强了大鼠和人类胰岛的β细胞增殖，并且输注GLU+CLI的大鼠血清增强了葡萄糖的作用。输注结束6天后，葡萄糖耐量、β细胞增殖和胰岛体积均恢复到正常水平。
结论/解读：葡萄糖和NEFA协同且可逆地促进β细胞增殖，部分是通过对β细胞的直接作用，且独立于分泌的胰岛素。
