Weisberg S, Leibel R, Tortoriello D V
Naomi Berrie Diabetes Center, Columbia University, New York, NY, USA.
Sher Institute for Reproductive Medicine, New York, NY, USA.
Nutr Diabetes. 2016 Apr 25;6(4):e205. doi: 10.1038/nutd.2016.13.
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 (Lepr(db/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.
2型糖尿病源于肥胖相关的胰岛素抵抗，在遗传易感性个体中，可能会伴随胰腺β细胞功能衰竭，进而使高血糖症进一步恶化。我们团队及其他团队最近的研究表明，天然多酚姜黄素可减轻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。尽管姜黄素存在几个潜在的下游分子靶点，但现在已知它是蛋白酶体活性的直接抑制剂。我们现在表明，姜黄素还可预防Kaliss背景下未代偿性肥胖相关胰岛素抵抗（Lepr(db/db)）小鼠模型中的β细胞功能衰竭。
在这种情况下，饮食中补充姜黄素可预防高血糖症，增加胰岛素分泌和瘦体重，并延长寿命。此外，我们表明，用两种分子结构不同的蛋白酶体抑制剂（雷公藤红素和环氧霉素）进行短期体内治疗，可通过增加胰岛素分泌和胰岛素敏感性来逆转β细胞功能衰竭小鼠的高血糖症。
这些研究表明，蛋白酶体抑制剂可能对糖尿病患者有用，因为它既能改善β细胞功能，又能缓解胰岛素抵抗。
