Matschinsky F M, Rujanavech C, Pagliara A, Norfleet W T
J Clin Invest. 1980 Jan;65(1):207-18. doi: 10.1172/JCI109652.
The effects of starvation and refeeding and of obesity on pancreatic alpha2- and beta-cell responses to glucose or tolbutamide were studied with the isolated rat or mouse pancreas perfused with an amino acid mixture in the presence and absence of glucose. It was observed that the physiological adaptation to a regimen of fasting and realimentation and to obesity differed greatly in the two types of endocrine cells. Whereas beta-cells of rats showed a dramatic reduction of glucose- and tolbutamide-stimulated insulin release during starvation that was reversed by refeeding, alpha2-cells preserved their response to stimulators and inhibitors during this experimental manipulation. Amino acid stimulation of glucagon release occurred equally well with the pancreas from fed and starved rats and was suppressed efficiently by glucose and tolbutamide in both nutritional states. Surprisingly, the rate of onset of glucose suppression of alpha2-cells was significantly higher in the fasted than in the fed state. This glucose hypersensitivity was apparent 2 d after after food deprivation and had disappeared again on the 2nd d of refeeding. In the pancreas from animals starved for 3 d, glucose and tolbutamide suppression of alpha2-cells took place in the absence of demonstrable changes of insulin release. In the isolated perfused pancreas taken from the hyperphagic obese hyperglycemic mouse (C57 Black/6J; ob/ob), the observed rate of insulin secretion as a result of a combined stimulus of amino acids and glucose and of glucagon release stimulated by amino acids was about four times higher than achieved by the pancreas of lean controls. However, glucose was unable to suppress the alpha2-cells in the pancreas of obese animals, in spite of the hypersection of the beta-cells, again in contrast to the alpha2-cells of controls that were readily inhibited by glucose. These data imply that the acute suppression of alpha2-cells by glucose is largely independent of a concomitant surge of extracellular insulin levels and that the adaptation of the islet organ to starvation leads to decreased glucose sensitivity of beta-cells, which contrasts with an improved glucose responsiveness of alpha2-cells. However, hyperphagia, which is assumed to be the primary abnormality in the ob/ob mouse, leads to overproduction of insulin and glucagon by the pancreas while greatly reducing the alpha2-cell sensitivity to glucose. An attempt is made to incorporate these data on starvation, refeeding, and obesity, as well as previous results with experimental diabetes, in a comprehensive picture describing a regulative principle underlying the glucose responsivness of alpha2-cells.
在有或无葡萄糖存在的情况下，用氨基酸混合物灌注分离的大鼠或小鼠胰腺，研究饥饿、再喂养以及肥胖对胰腺α2细胞和β细胞对葡萄糖或甲苯磺丁脲反应的影响。观察到，在这两种内分泌细胞中，对禁食和再喂养方案以及肥胖的生理适应性差异很大。饥饿期间，大鼠的β细胞受葡萄糖和甲苯磺丁脲刺激的胰岛素释放显著减少，再喂养后恢复正常，而α2细胞在该实验操作过程中保留了对刺激物和抑制剂的反应。喂食和饥饿大鼠的胰腺对氨基酸刺激胰高血糖素释放的反应相同，在两种营养状态下，葡萄糖和甲苯磺丁脲均能有效抑制这种反应。令人惊讶的是，禁食状态下α2细胞对葡萄糖抑制的起始速率显著高于喂食状态。这种葡萄糖超敏反应在禁食2天后明显，再喂养第2天又消失。在饥饿3天的动物的胰腺中，葡萄糖和甲苯磺丁脲对α2细胞的抑制发生在胰岛素释放无明显变化的情况下。在从食欲亢进的肥胖高血糖小鼠（C57 Black/6J；ob/ob）分离的灌注胰腺中，观察到氨基酸和葡萄糖联合刺激导致的胰岛素分泌速率以及氨基酸刺激的胰高血糖素释放速率约为瘦对照胰腺的四倍。然而，尽管β细胞分泌过多，但葡萄糖无法抑制肥胖动物胰腺中的α2细胞，这与对照的α2细胞容易被葡萄糖抑制再次形成对比。这些数据表明，葡萄糖对α2细胞的急性抑制在很大程度上独立于细胞外胰岛素水平的同时升高，胰岛器官对饥饿的适应导致β细胞葡萄糖敏感性降低，这与α2细胞葡萄糖反应性提高形成对比。然而，被认为是ob/ob小鼠主要异常的食欲亢进，导致胰腺胰岛素和胰高血糖素过度产生，同时大大降低α2细胞对葡萄糖的敏感性。本文试图将这些关于饥饿、再喂养和肥胖的数据，以及先前实验性糖尿病的结果，纳入一个全面的描述α2细胞葡萄糖反应性调节原则的图景中。
