Proteasome inhibitors, including curcumin, improve pancreatic β-cell function and insulin sensitivity in diabetic mice.
Proteasome inhibitors, including curcumin, improve pancreatic β-cell function and insulin sensitivity in diabetic mice.
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DOI：
10.1038/nutd.2016.13
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发表时间：
2016-04-25
影响因子：
6.1
通讯作者：
Tortoriello DV
中科院分区：
文献类型：
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作者：
Weisberg S;Leibel R;Tortoriello DV
2型糖尿病源于肥胖相关的胰岛素抵抗，在遗传易感者中，可发生伴随的胰腺β细胞衰竭，这进一步加剧了高血糖症。我们小组和其他人最近的工作表明，天然多酚姜黄素减弱高胰岛素血症或代偿性2型糖尿病小鼠模型中胰岛素抵抗和高血糖症的发展。虽然姜黄素存在几个潜在的下游分子靶点，但它现在被认为是蛋白酶体活性的直接抑制剂。我们现在表明，姜黄素还可以预防未补偿的肥胖相关胰岛素抵抗小鼠模型中的β细胞衰竭（Kaliss背景下的Leprdb/db）。在这种情况下，膳食补充姜黄素可以预防高血糖症，增加胰岛素的产生和瘦体重，并延长寿命。此外，我们还发现，低剂量的两种分子上不同的蛋白酶体抑制剂雷公藤红素和环氧霉素的短期体内治疗通过增加胰岛素产生和胰岛素敏感性来逆转β细胞衰竭小鼠的高血糖症。这些研究表明，蛋白酶体抑制剂可能通过改善β细胞功能和缓解胰岛素抵抗而对糖尿病患者有用。
Type 2 diabetes stems from obesity-associated insulin resistance, and in the genetically susceptible, concomitant pancreatic β-cell failure can occur, which further exacerbates hyperglycemia. Recent work by our group and others has shown that the natural polyphenol curcumin attenuates the development of insulin resistance and hyperglycemia in mouse models of hyperinsulinemic or compensated type 2 diabetes. Although several potential downstream molecular targets of curcumin exist, it is now recognized to be a direct inhibitor of proteasome activity. We now show that curcumin also prevents β-cell failure in a mouse model of uncompensated obesity-related insulin resistance (Leprdb/db on the Kaliss background). In this instance, dietary supplementation with curcumin prevented hyperglycemia, increased insulin production and lean body mass, and prolonged lifespan. In addition, we show that short-term in vivo treatment with low dosages of two molecularly distinct proteasome inhibitors celastrol and epoxomicin reverse hyperglycemia in mice with β-cell failure by increasing insulin production and insulin sensitivity. These studies suggest that proteasome inhibitors may prove useful for patients with diabetes by improving both β-cell function and relieving insulin resistance.