Diabetes Unit, Hadassah-Hebrew Univ. Medical Center, Jerusalem 12000, Israel 91120.
Am J Physiol Endocrinol Metab. 2013 May 15;304(10):E1023-34. doi: 10.1152/ajpendo.00036.2013. Epub 2013 Mar 19.
β-Cell mitochondrial dysfunction as well as proinflammatory cytokines have been suggested to contribute to reduced glucose-stimulated insulin secretion (GSIS) in type 2 diabetes. We recently demonstrated that Cohen diabetic sensitive (CDs) rats fed a high-sucrose, low-copper diet (HSD) developed hyperglycemia and reduced GSIS in association with peri-islet infiltration of fat and interleukin (IL)-1β-expressing macrophages, whereas CD resistant (CDr) rats remained normoglycemic on HSD. We examined: 1) the correlation between copper concentration in the HSD and progression, prevention, and reversion of hyperglycemia in CDs rats, 2) the relationship between activity of the copper-dependent, respiratory-chain enzyme cytochrome c oxidase (COX), infiltration of fat, IL-1β-expressing macrophages, and defective GSIS in hyperglycemic CDs rats. CDs and CDr rats were fed HSD or copper-supplemented HSD before and during hyperglycemia development. Blood glucose and insulin concentrations were measured during glucose tolerance tests. Macrophage infiltration and IL-1β expression were evaluated in pancreatic sections by electron-microscopy and immunostaining. COX activity was measured in pancreatic sections and isolated islets. In CDs rats fed HSD, GSIS and islet COX activity decreased, while blood glucose and infiltration of fat and IL-1β-expressing macrophages increased with time on HSD (P < 0.01 vs. CDr-HSD rats, all parameters, respectively). CDs rats maintained on copper-supplemented HSD did not develop hyperglycemia, and in hyperglycemic CDs rats, copper supplementation restored GSIS and COX activity, reversed hyperglycemia and infiltration of fat and IL-1β-expressing macrophages (P < 0.01 vs. hyperglycemic CDs-HSD rats, all parameters, respectively). We provide novel evidence for a critical role of low dietary copper in diminished GSIS of susceptible CDs rats involving the combined consequence of reduced islet COX activity and pancreatic low-grade inflammation.
β 细胞线粒体功能障碍以及促炎细胞因子被认为导致 2 型糖尿病患者葡萄糖刺激的胰岛素分泌（GSIS）减少。我们最近证明，给予高蔗糖、低铜饮食（HSD）的 Cohen 糖尿病敏感（CDs）大鼠发展为高血糖和 GSIS 减少，与胰岛周围浸润的脂肪和表达白细胞介素（IL）-1β的巨噬细胞有关，而 CD 抵抗（CDr）大鼠在 HSD 上仍保持正常血糖。我们研究了：1）HSD 中的铜浓度与 CDs 大鼠高血糖的进展、预防和逆转之间的相关性，2）活性铜依赖性、呼吸链酶细胞色素 c 氧化酶（COX）、脂肪浸润、表达 IL-1β的巨噬细胞和高血糖 CDs 大鼠中受损的 GSIS 之间的关系。在高血糖发生之前和期间，CDs 和 CDr 大鼠分别用 HSD 或补充铜的 HSD 喂养。在葡萄糖耐量试验期间测量血糖和胰岛素浓度。通过电子显微镜和免疫染色评估胰腺切片中的巨噬细胞浸润和 IL-1β表达。在胰腺切片和分离的胰岛中测量 COX 活性。在给予 HSD 的 CDs 大鼠中，随着时间的推移，GSIS 和胰岛 COX 活性降低，而血糖以及脂肪和表达 IL-1β的巨噬细胞浸润增加（与 CDr-HSD 大鼠相比，所有参数均 P <0.01）。继续给予补充铜的 HSD 的 CDs 大鼠未发生高血糖，并且在高血糖 CDs 大鼠中，铜补充恢复了 GSIS 和 COX 活性，逆转了高血糖以及脂肪和表达 IL-1β的巨噬细胞浸润（与高血糖 CDs-HSD 大鼠相比，所有参数均 P <0.01）。我们提供了新的证据，表明低膳食铜在易感 CDs 大鼠 GSIS 减少中起关键作用，涉及胰岛 COX 活性降低和胰腺低度炎症的综合后果。
