Black H E, Rosenblum I Y, Capen C C
Am J Pathol. 1980 Feb;98(2):295-310.
Adult beagle dogs were infused intravenously with alloxan (50 mg/kg) and streptozotocin (30 mg/kg) in order to investigate sequential changes in plasma glucose, insulin, glucagon, and cortisol. These biochemical findings were correlated with ultrastructural alterations in pancreatic islets. Following infusion, the dogs became hyperglycemic by 2 hours, severely hypoglycemic by 6 to 14 hours, and permanently hyperglycemic by 24 hours. Plasma immunoreactive insulin increased sharply from 6 to 10 hours, then declined to nearly undetectable levels by 24 hours. Ultrastructurally, beta cells at 2 hours had clumped nuclear chromatin, vacuolated mitochondria, and dilated individual profiles of endoplasmic reticulum. Secretory granules appeared swollen but retained their internal cores. Degeneration of beta cells was severe after 10 hours, and plasma membranes of beta cells were disrupted by 24 hours. The cytoplasmic area of adjacent beta cells coalesced and had accumulations of membranous debris, lipofuscin, and autophagic vacuoles. Alpha and delta cells appeared to be unaffected. Plasma glucagon levels decreased markedly at 10 hours and were related reciprocally to changes in plasma insulin. Pancreatic islets in dogs with chronic (16 months) diabetes were small and composed primarily of granulated alpha and delta cells. Poorly granulated beta cells with degenerative changes were present in an occasional islet. The results of this investigation demonstrated that the combined administration of a single dose of alloxan and streptozotocin selectively destroyed the beta cells, while alpha and delta cells of the islets of Langerhans remained unaltered. Pathologic evidence of toxicity was not present in other organs. Chemically induced diabetes mellitus in dogs is a reproducible animal model that should prove useful in studies requiring repeated experimental manipulations or sampling of biologic fluids in order to evaluate the long-term effects of different routes of delivery or preparations of insulin to control the persistent hyperglycemia.
为了研究血浆葡萄糖、胰岛素、胰高血糖素和皮质醇的序贯变化，给成年比格犬静脉注射四氧嘧啶（50毫克/千克）和链脲佐菌素（30毫克/千克）。这些生化结果与胰岛的超微结构改变相关。注射后，犬在2小时时出现高血糖，6至14小时时出现严重低血糖，24小时时出现永久性高血糖。血浆免疫反应性胰岛素在6至10小时急剧增加，然后在24小时时降至几乎检测不到的水平。超微结构上，2小时时β细胞的核染色质聚集，线粒体空泡化，内质网的单个轮廓扩张。分泌颗粒似乎肿胀但保留其内部核心。10小时后β细胞变性严重，24小时时β细胞的质膜被破坏。相邻β细胞的细胞质区域融合，并伴有膜碎片、脂褐素和自噬空泡的积累。α细胞和δ细胞似乎未受影响。血浆胰高血糖素水平在10小时时显著下降，与血浆胰岛素的变化呈反比。患有慢性（16个月）糖尿病的犬的胰岛较小，主要由颗粒状的α细胞和δ细胞组成。偶尔有胰岛中存在颗粒较少且有退行性变化的β细胞。本研究结果表明，单剂量四氧嘧啶和链脲佐菌素联合给药选择性地破坏了β细胞，而胰岛的α细胞和δ细胞保持不变。其他器官未出现毒性的病理证据。化学诱导的犬糖尿病是一种可重复的动物模型，在需要重复进行实验操作或采集生物体液以评估不同给药途径或胰岛素制剂对控制持续性高血糖的长期影响的研究中应会证明有用。
