Larsen M O, Rolin B, Gotfredsen C F, Carr R D, Holst J J
Department of Pharmacology Research 1, Pharmacology, Research and Development, Novo Nordisk Park, F6.1.30, Novo Nordisk, 2760 Måløv, Denmark.
Diabetologia. 2004 Nov;47(11):1873-8. doi: 10.1007/s00125-004-1546-9. Epub 2004 Nov 24.
AIMS/HYPOTHESIS: A progressive loss of beta cell function and mass are important contributory factors in the development and progression of type 2 diabetes. The aim of this study was to evaluate the effects of a primary reduction in beta cell mass on beta cell function in vivo and in the perfused pancreas and to relate these characteristics to beta cell mass.
The beta cell mass of six Göttingen minipigs was reduced chemically (using 67 mg/kg nicotinamide and 125 mg/kg streptozotocin). Six untreated minipigs were kept as control animals. Insulin responses were evaluated in vivo using the mixed meal tolerance test (2 g/kg oral glucose) and in the isolated perfused pancreata from the same animals by stimulation with glucose, glucagon-like peptide-1 or arginine.
Beta cell mass was reduced in the beta-cell-reduced animals compared with the control minipigs (182+/-76 vs 464+/-156 mg, p<0.01). AUC(glucose) was increased in the beta-cell-reduced animals (1383+/-385 vs 853+/-113 mmol.l(-1).min in control minipigs, p<0.01), as was the insulin response to oral glucose per unit of beta cell mass (123+/-84 vs 56+/-24 pmol.l(-1).min.mg(-1), p<0.05). Total in vitro insulin secretion was increased per unit of beta cell mass in nicotinamide + streptozotocin pancreata compared to controls (83.7+/-45.9 vs 34.6+/-14.4 nmol/mg beta cells, p<0.05) with responses to glucose and glucagon-like peptide-1 showing a partial compensation for reduced beta cell mass, whereas no compensation was seen in response to arginine.
CONCLUSIONS/INTERPRETATION: A primary reduction in beta cell mass impairs glucose tolerance and leads to a compensatory increase in insulin secretion from the remaining beta cells after oral glucose in vivo, which is even more apparent in the perfused pancreas. It remains to be determined whether this compensation can be maintained in the long term.
目的/假设：β细胞功能和数量的逐渐丧失是2型糖尿病发生和发展的重要促成因素。本研究的目的是评估β细胞数量原发性减少对体内及灌注胰腺中β细胞功能的影响，并将这些特征与β细胞数量相关联。
对6只哥廷根小型猪的β细胞数量进行化学性减少（使用67mg/kg烟酰胺和125mg/kg链脲佐菌素）。6只未处理的小型猪作为对照动物。通过混合餐耐量试验（2g/kg口服葡萄糖）在体内评估胰岛素反应，并通过用葡萄糖、胰高血糖素样肽-1或精氨酸刺激，在来自相同动物的离体灌注胰腺中评估胰岛素反应。
与对照小型猪相比，β细胞数量减少的动物的β细胞数量减少（182±76mg对464±156mg，p<0.01）。β细胞数量减少的动物的葡萄糖曲线下面积（AUC）增加（对照小型猪为853±113mmol·l⁻¹·min，β细胞数量减少的动物为1383±385mmol·l⁻¹·min，p<0.01），每单位β细胞数量对口服葡萄糖的胰岛素反应也增加（56±24pmol·l⁻¹·min·mg⁻¹对123±84pmol·l⁻¹·min·mg⁻¹，p<0.05）。与对照相比，烟酰胺+链脲佐菌素处理的胰腺中每单位β细胞数量的体外总胰岛素分泌增加（34.6±14.4nmol/mgβ细胞对83.7±45.9nmol/mgβ细胞，p<0.05），对葡萄糖和胰高血糖素样肽-1的反应显示出对β细胞数量减少的部分补偿，而对精氨酸的反应未观察到补偿。
结论/解读：β细胞数量的原发性减少损害葡萄糖耐量，并导致体内口服葡萄糖后剩余β细胞胰岛素分泌的代偿性增加，这在灌注胰腺中更为明显。这种代偿能否长期维持仍有待确定。
