Höppener J W, Oosterwijk C, Nieuwenhuis M G, Posthuma G, Thijssen J H, Vroom T M, Ahrén B, Lips C J
Department of Internal Medicine, University Hospital Utrecht, University of Utrecht, Medical School, The Netherlands.
Diabetologia. 1999 Apr;42(4):427-34. doi: 10.1007/s001250051175.
AIMS/HYPOTHESIS: Type II (non-insulin-dependent) diabetes mellitus is a multifactorial disease in which pancreatic islet amyloid is a characteristic histopathological finding. Islet amyloid fibrils consist of the beta-cell protein "islet amyloid polypeptide" (IAPP)/"amylin". Unlike human IAPP (hIAPP), mouse IAPP cannot form amyloid. In previously generated transgenic mice, high expression of hIAPP as such did not induce islet amyloid formation. To further explore the potential diabetogenic role of amyloidogenic IAPP, we introduced a diabetogenic trait ("ob" mutation) in hIAPP transgenic mice.
Plasma concentrations of IAPP, insulin and glucose were determined at 3.5 (t1), 6 (t2), and 16-19 months of age (t3). At t3, the mice were killed and the pancreas was analysed (immuno)histochemically.
In non-transgenic ob/ob mice, insulin resistance caused a compensatory increase in insulin production, normalizing the initial hyperglycaemia. In transgenic ob/ob mice, concurrent increase in hIAPP production resulted in extensive islet amyloid formation (more often and more extensive than in transgenic non-ob/ob mice), insulin insufficiency and persistent hyperglycaemia: At t3, plasma insulin levels in transgenic ob/ob mice with amyloid were fourfold lower than in non-transgenic ob/ob mice (p < 0.05), and plasma glucose concentrations in transgenic ob/ ob mice were almost twofold higher (p < 0.05). In addition, the degree of islet amyloid formation in ob/ob mice was positively correlated to the glucose:insulin ratio (r(s) = 0.53, p < 0.05).
CONCLUSION/INTERPRETATION: Islet amyloid is a secondary diabetogenic factor which can be both a consequence of insulin resistance and a cause of insulin insufficiency. [Diabetol
目的/假设：II型（非胰岛素依赖型）糖尿病是一种多因素疾病，其中胰岛淀粉样变是其特征性组织病理学表现。胰岛淀粉样纤维由β细胞蛋白“胰岛淀粉样多肽”（IAPP）/“胰淀素”组成。与人类IAPP（hIAPP）不同，小鼠IAPP不能形成淀粉样变。在先前构建的转基因小鼠中，单纯hIAPP的高表达并未诱导胰岛淀粉样变的形成。为了进一步探究具有淀粉样变形成能力的IAPP的潜在致糖尿病作用，我们在hIAPP转基因小鼠中引入了一种致糖尿病性状（“ob”突变）。
在3.5月龄（t1）、6月龄（t2）和16 - 19月龄（t3）时测定血浆IAPP、胰岛素和葡萄糖浓度。在t3时，处死小鼠并对胰腺进行（免疫）组织化学分析。
在非转基因ob/ob小鼠中，胰岛素抵抗导致胰岛素分泌代偿性增加，使初始高血糖恢复正常。在转基因ob/ob小鼠中，hIAPP分泌同时增加导致广泛的胰岛淀粉样变形成（比转基因非ob/ob小鼠更常见且更广泛）、胰岛素分泌不足和持续性高血糖：在t3时，有淀粉样变的转基因ob/ob小鼠的血浆胰岛素水平比非转基因ob/ob小鼠低四倍（p < 0.05），转基因ob/ob小鼠的血浆葡萄糖浓度几乎高两倍（p < 0.05）。此外，ob/ob小鼠中胰岛淀粉样变形成的程度与葡萄糖:胰岛素比值呈正相关（r(s) = 0.53，p < 0.05）。
结论/解读：胰岛淀粉样变是一种继发性致糖尿病因素，它既可能是胰岛素抵抗的结果，也可能是胰岛素分泌不足的原因。[糖尿病学
