Pancreatic islet amyloidosis, β-cell apoptosis, and α-cell proliferation are determinants of islet remodeling in type-2 diabetic baboons
Pancreatic islet amyloidosis, β-cell apoptosis, and α-cell proliferation are determinants of islet remodeling in type-2 diabetic baboons
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DOI：
10.1073/pnas.0906471106
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发表时间：
2009-08-18
影响因子：
11.1
通讯作者：
Folli, Franco
中科院分区：
文献类型：
--
作者：
Guardado-Mendoza, Rodolfo;Davalli, Alberto M.;Folli, Franco
β细胞功能障碍是2型糖尿病高血糖发生的重要因素，胰岛淀粉样变性（IA）被认为是胰岛素分泌受损的主要原因之一。本研究的目的是评估 IA 与代谢参数的相关性及其对狒狒胰岛重塑和相对内分泌细胞体积的影响。我们对 150 只具有不同代谢状态的狒狒进行了胰淀素肽测序，确定了纤维化倾向，并评估了胰腺组织学、临床和生化特征以及内分泌细胞增殖和凋亡。狒狒的胰淀素序列与人类有 92% 相似，并且显示出可叠加的原纤维形成倾向。 IA 严重程度与空腹血糖 (FPG)（r = 0.662，P < 0.001）和 HbA1c（r = 0.726，P < 0.001）以及游离脂肪酸、胰高血糖素值、降低的稳态模型评估 (HOMA) 胰岛素抵抗和 HOMA-B 相关。 IA 严重程度与相对 β 细胞体积减少、相对 α 细胞体积增加和高胰高血糖素血症相关。这些结果强烈支持这样的观点，即 IA 和 β 细胞凋亡与 α 细胞增殖和肥大相结合，是狒狒（2 型糖尿病的非人灵长类动物模型）中朗格汉斯胰岛“功能失调性重塑”和高血糖的关键决定因素。IA 最重要的决定因素是年龄和 FPG（R-2 = 0.519，P < 0.0001），并且不同FPG 水平对于预测 IA 严重程度具有敏感性和特异性。最后，以年龄和 FPG 作为所需变量，生成了胰岛淀粉样蛋白严重程度的预测模型。
beta-Cell dysfunction is an important factor in the development of hyperglycemia of type-2 diabetes mellitus, and pancreatic islet amyloidosis (IA) has been postulated to be one of the main contributors to impaired insulin secretion. The aim of this study was to evaluate the correlation of IA with metabolic parameters and its effect on islets of Langerhans remodeling and relative endocrine-cell volume in baboons. We sequenced the amylin peptide, determined the fibrillogenic propensities, and evaluated pancreatic histology, clinical and biochemical characteristics, and endocrine cell proliferation and apoptosis in 150 baboons with different metabolic status. Amylin sequence in the baboon was 92% similar to humans and showed superimposable fibrillogenic propensities. IA severity correlated with fasting plasma glucose (FPG) (r = 0.662, P < 0.001) and HbA1c (r = 0.726, P < 0.001), as well as with free fatty acid, glucagon values, decreased homeostasis model assessment (HOMA) insulin resistance, and HOMA-B. IA severity was associated with a decreased relative beta-cell volume, and increased relative alpha-cell volume and hyperglucagonemia. These results strongly support the concept that IA and beta-cell apoptosis in concert with alpha-cell proliferation and hypertrophy are key determinants of islets of Langerhans "dysfunctional remodeling'' and hyperglycemia in the baboon, a nonhuman primate model of type-2 diabetes mellitus. The most important determinants of IA were age and FPG (R-2 = 0.519, P < 0.0001), and different FPG levels were sensitive and specific to predict IA severity. Finally, a predictive model for islet amyloid severity was generated with age and FPG as required variables.