Vidal J, Verchere C Bruce, Andrikopoulos S, Wang F, Hull R L, Cnop M, Olin K L, LeBoeuf R C, O'Brien K D, Chait A, Kahn S E
Division of Metabolism, Endocrinology and Nutrition, Department of Medicine, University of Washington, Seattle, Washington, USA.
Diabetologia. 2003 Jan;46(1):71-9. doi: 10.1007/s00125-002-0984-5. Epub 2003 Jan 9.
AIMS/HYPOTHESIS: Islet amyloid deposits are present in over 85% of Type 2 diabetic patients and have been suggested to be pathogenic. The mechanism that converts islet amyloid polypeptide (IAPP), the unique component of these deposits, into amyloid fibrils in vivo is not known. The amino acid sequence of IAPP is critical but insufficient for beta-pleated sheet formation. As apolipoprotein E (apoE), another component of islet amyloid deposits, plays a critical role in amyloid formation in Alzheimer's disease, we hypothesised that apoE could play an important role in islet amyloid formation.
Transgenic mice expressing the human form of IAPP ( hIAPP (+/0)) were crossbred with apoE deficient ( apoE (-/-)) mice and followed for 12 months, at which time the prevalence and severity of islet amyloid, as well as plasma glucose, hIAPP, immunoreactive insulin (IRI) and lipid concentrations were measured.
The prevalence and severity of islet amyloid after one year of follow up were comparable among hIAPP (+/0) mice that were apoE (+/+), apoE (+/-) or apoE (-/-). Differences in glucose tolerance, lipid abnormalities or changes in pancreatic content or plasma concentrations of hIAPP and/or IRI did not account for these findings.
CONCLUSION/INTERPRETATION: Our data shows that, unlike in the localized amyloidosis in the brain characteristic of Alzheimer's disease, apoE is not critical for islet amyloid formation in a transgenic mouse model of Type 2 diabetes mellitus. These results indicate that the mechanisms of localised amyloid formation probably vary among different amyloid-associated disorders. Therefore, therapeutic strategies targeting apoE might not apply equally to patients with different amyloid associated diseases.
目的/假设：胰岛淀粉样沉积物存在于超过85%的2型糖尿病患者中，并被认为具有致病性。将这些沉积物的独特成分胰岛淀粉样多肽（IAPP）在体内转化为淀粉样纤维的机制尚不清楚。IAPP的氨基酸序列对于β折叠片层的形成至关重要，但并不充分。由于胰岛淀粉样沉积物的另一种成分载脂蛋白E（apoE）在阿尔茨海默病的淀粉样形成中起关键作用，我们推测apoE可能在胰岛淀粉样形成中起重要作用。
将表达人源形式IAPP（hIAPP(+/0)）的转基因小鼠与apoE缺陷（apoE(-/-)）小鼠杂交，并随访12个月，此时测量胰岛淀粉样变的发生率和严重程度，以及血浆葡萄糖、hIAPP、免疫反应性胰岛素（IRI）和脂质浓度。
随访一年后，apoE(+/+)、apoE(+/-)或apoE(-/-)的hIAPP(+/0)小鼠中胰岛淀粉样变的发生率和严重程度相当。葡萄糖耐量、脂质异常或胰腺中hIAPP和/或IRI含量或血浆浓度的变化不能解释这些结果。
结论/解读：我们的数据表明，与阿尔茨海默病特征性的脑局部淀粉样变性不同，在2型糖尿病转基因小鼠模型中，apoE对胰岛淀粉样形成并不关键。这些结果表明，局部淀粉样形成的机制可能在不同的淀粉样相关疾病中有所不同。因此，针对apoE的治疗策略可能不适用于所有不同的淀粉样相关疾病患者。
