Steil G M, Trivedi N, Jonas J C, Hasenkamp W M, Sharma A, Bonner-Weir S, Weir G C
Section of Islet Transplantation and Cell Biology, Research Division, Joslin Diabetes Center, Boston, Massachusetts 02215, USA.
Am J Physiol Endocrinol Metab. 2001 May;280(5):E788-96. doi: 10.1152/ajpendo.2001.280.5.E788.
Although type 2 diabetes mellitus is associated with insulin resistance, many individuals compensate by increasing insulin secretion. Putative mechanisms underlying this compensation were assessed in the present study by use of 4-day glucose (GLC; 35% Glc, 2 ml/h) and lipid (LIH; 10% Intralipid + 20 U/ml heparin; 2 ml/h) infusions to rats. Within 2 days of beginning the infusion of either lipid or glucose, plasma glucose profiles were normalized (relative to saline-infused control rats; SAL; 0.45% 2 ml/h). During glucose infusion, plasma glucose was maintained in the normal range by an approximately twofold increase in plasma insulin and an approximately 80% increase in beta-cell mass. During LIH infusion, glucose profiles were also maintained in the normal range. Plasma insulin responses during feeding were doubled, and beta-cell mass increased 54%. For both groups, the increase in beta-cell mass was associated with increased beta-cell proliferation (98% increase during GLC and 125% increase during LIH). At the end of the 4-day infusions, no significant changes were observed in islet-specific gene transcription (i.e., the expression of islet hormone genes, glucose metabolism genes, and insulin transcription factors were unaffected). Two days after termination of the infusions, the glucose-stimulated plasma insulin response was increased approximately 67% in glucose-infused animals. No sustained effect on insulin secretory capacity was observed in the LIH animals. The increase in plasma insulin response after glucose infusion was achieved in the absence of any change in insulin clearance. We conclude that, in rats, an increase in insulin demand after an increase in glucose appearance or free fatty acid leads to an increase in beta-cell mass, mediated in part by an increase in beta-cell proliferation, and that these compensatory changes lead to increased insulin secretion, normal plasma glucose levels, and the maintenance of normal islet gene expression.
尽管2型糖尿病与胰岛素抵抗有关，但许多个体通过增加胰岛素分泌来进行代偿。在本研究中，通过对大鼠进行为期4天的葡萄糖（GLC；35%葡萄糖，2 ml/h）和脂质（LIH；10%英脱利匹特+20 U/ml肝素；2 ml/h）输注，评估了这种代偿的潜在机制。在开始输注脂质或葡萄糖的2天内，血浆葡萄糖水平恢复正常（相对于输注生理盐水的对照大鼠；SAL；0.45% 2 ml/h）。在葡萄糖输注期间，血浆胰岛素增加约两倍，β细胞量增加约80%，从而使血浆葡萄糖维持在正常范围内。在LIH输注期间，葡萄糖水平也维持在正常范围内。进食期间的血浆胰岛素反应加倍，β细胞量增加54%。对于两组，β细胞量的增加均与β细胞增殖增加有关（GLC期间增加98%，LIH期间增加125%）。在4天输注结束时，未观察到胰岛特异性基因转录有显著变化（即胰岛激素基因、葡萄糖代谢基因和胰岛素转录因子的表达未受影响）。输注终止2天后，葡萄糖输注动物的葡萄糖刺激的血浆胰岛素反应增加了约67%。在LIH动物中未观察到对胰岛素分泌能力的持续影响。葡萄糖输注后血浆胰岛素反应的增加是在胰岛素清除率无任何变化的情况下实现的。我们得出结论，在大鼠中，葡萄糖出现或游离脂肪酸增加后胰岛素需求的增加会导致β细胞量增加，部分是由β细胞增殖增加介导的，并且这些代偿性变化会导致胰岛素分泌增加、血浆葡萄糖水平正常以及胰岛基因表达维持正常。
