Division of Metabolism, Endocrinology and Nutrition, VA Puget Sound Health Care System (151), 1660 South Columbian Way, Seattle, WA 98108, USA.
Diabetologia. 2011 Jul;54(7):1756-65. doi: 10.1007/s00125-011-2143-3. Epub 2011 Apr 12.
AIMS/HYPOTHESIS: In type 2 diabetes, aggregation of islet amyloid polypeptide (IAPP) into amyloid is associated with beta cell loss. As IAPP is co-secreted with insulin, we hypothesised that IAPP secretion is necessary for amyloid formation and that treatments that increase insulin (and IAPP) secretion would thereby increase amyloid formation and toxicity. We also hypothesised that the unique properties of the glucagon-like peptide-1 (GLP-1) receptor agonist exendin-4 to maintain or increase beta cell mass would offset the amyloid-induced toxicity.
Islets from amyloid-forming human IAPP transgenic and control non-transgenic mice were cultured for 48 h in 16.7 mmol/l glucose alone (control) or with exendin-4, potassium chloride (KCl), diazoxide or somatostatin. Human IAPP and insulin release, amyloid deposition, beta cell area/islet area, apoptosis and AKT phosphorylation levels were determined.
In control human IAPP transgenic islets, amyloid formation was associated with increased beta cell apoptosis and beta cell loss. Increasing human IAPP release with exendin-4 or KCl increased amyloid deposition. However, while KCl further increased beta cell apoptosis and beta cell loss, exendin-4 did not. Conversely, decreasing human IAPP release with diazoxide or somatostatin limited amyloid formation and its toxic effects. Treatment with exendin-4 was associated with an increase in AKT phosphorylation compared with control and KCl-treated islets.
CONCLUSIONS/INTERPRETATION: IAPP release is necessary for islet amyloid formation and its toxic effects. Thus, use of insulin secretagogues to treat type 2 diabetes may result in increased islet amyloidogenesis and beta cell death. However, the AKT-associated anti-apoptotic effects of GLP-1 receptor agonists such as exendin-4 may limit the toxic effects of increased islet amyloid.
目的/假设：在 2 型糖尿病中，胰岛淀粉样多肽（IAPP）的聚集形成淀粉样变为与β细胞丢失有关。由于 IAPP 与胰岛素共同分泌，我们假设 IAPP 分泌对于淀粉样形成是必要的，并且增加胰岛素（和 IAPP）分泌的治疗方法将因此增加淀粉样形成和毒性。我们还假设胰高血糖素样肽-1（GLP-1）受体激动剂 exendin-4 维持或增加β细胞质量的独特特性将抵消淀粉样诱导的毒性。
将来自形成淀粉样的人 IAPP 转基因和对照非转基因小鼠的胰岛在 16.7mmol/l 葡萄糖中单独培养 48 小时（对照）或用 exendin-4、氯化钾（KCl）、二氮嗪或生长抑素培养。测定人 IAPP 和胰岛素释放、淀粉样沉积、β细胞面积/胰岛面积、细胞凋亡和 AKT 磷酸化水平。
在对照的人 IAPP 转基因胰岛中，淀粉样形成与β细胞凋亡和β细胞丢失增加有关。用 exendin-4 或 KCl 增加人 IAPP 释放会增加淀粉样沉积。然而，虽然 KCl 进一步增加了β细胞凋亡和β细胞丢失，但 exendin-4 没有。相反，用二氮嗪或生长抑素减少人 IAPP 释放会限制淀粉样形成及其毒性作用。与对照和 KCl 处理的胰岛相比，用 exendin-4 处理与 AKT 磷酸化增加有关。
结论/解释：IAPP 释放对于胰岛淀粉样形成及其毒性作用是必要的。因此，使用胰岛素分泌剂治疗 2 型糖尿病可能会导致胰岛淀粉样形成增加和β细胞死亡。然而，GLP-1 受体激动剂如 exendin-4 的 AKT 相关抗凋亡作用可能会限制淀粉样增加的毒性作用。
