Dissociated insulinotropic sensitivity to glucose and carbachol in high-fat diet-induced insulin resistance in C57BL/6J mice
Dissociated insulinotropic sensitivity to glucose and carbachol in high-fat diet-induced insulin resistance in C57BL/6J mice
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DOI：
10.1016/s0026-0495(97)90175-x
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发表时间：
1997-01-01
影响因子：
9.8
通讯作者：
Sundler, F
中科院分区：
文献类型：
--
作者：
Ahren, B;Simonsson, E;Sundler, F
为了研究胰岛素敏感性降低后的胰岛功能，我们检查了C57 BL/6 J品系的小鼠，其基因型在代谢挑战时具有增加的发展胰岛素抵抗的倾向。这些小鼠接受高脂肪饮食（基于能量的58%脂肪）或对照饮食（11%脂肪）12周。高脂饮食组小鼠的体重比对照饮食组小鼠的体重显著增加（25.8 +/- 0.4 vs 21.3 +/- 0.2 g，P <0.001）。在高脂饮食1周后，已经出现了显著的高血糖症伴高胰岛素血症，表明胰岛素抵抗。12周后，高脂饮食治疗小鼠的血糖水平为7.5 +/- 0.1 mmol/L，对照组为6.5 +/- 0.1 mmol/L（P < .001）;相应的血浆胰岛素值分别为248 +/- 17和104 +/- 7 pmol/L（P < .001）。与对照组相比，给予高脂肪饮食的小鼠的总胆固醇、甘油三酯和游离脂肪酸（FFA）水平也有所升高。4、8和12周后，腹腔内注射葡萄糖（2.8、8.3或16.7 mmol/kg）或胆碱能激动剂卡巴胆碱（0.16或0.53 μ mol/kg）。4周或8周后，两组对葡萄糖的促胰岛素反应没有差异，而12周后，高脂饮食治疗的小鼠中葡萄糖诱导的胰岛素分泌明显受损（P < .001）。相反，在高脂饮食8周和12周后，卡巴胆碱刺激的胰岛素分泌增强（P <0.01），而卡巴胆碱刺激的胰高血糖素分泌没有显著改变。此外，高脂饮食12周后，在葡萄糖水平为8.3、11.1和16.7 mmol/L时，分离的胰岛的胰岛素分泌受损（P小于或等于0.05）。此外，胰岛形态检查免疫细胞化学使用胰岛素抗体和胰岛神经支配，如所揭示的免疫染色BF酪氨酸羟化酶（TH），神经肽Y（NPY），甘丙肽，血管活性肠多肽（VIP），和P物质（SP）的高脂饮食12周不受影响。然而，定量原位杂交显示，尽管B细胞质量和胰腺胰岛素含量没有改变，但高脂饮食引起胰岛素基因表达上调3.5倍（P <0.001）。我们得出结论，在C57 BL/6 J小鼠中，用高脂饮食治疗仅1周即可诱导胰岛素抵抗。这随后伴随着高血糖，增强卡巴胆碱刺激的胰岛素分泌，以及胰岛素基因表达增加但葡萄糖刺激的胰岛素分泌受损。我们认为，经过几周的时间，胰岛素抵抗伴随着增强的胰岛敏感性胆碱能激活和夸张的胰岛素基因表达，而失败的胰岛敏感性葡萄糖代表代偿失调。版权所有（C）1997 W.B.桑德斯公司
To study islet function following reduced insulin sensitivity, we examined mice of the C57BL/6J strain, the genotype of which carries an increased propensity to develop insulin resistance when metabolically challenged. The mice received either a high-fat diet (58% fat on an energy basis) or a control diet (11% fat) for 12 weeks. The body weight of mice on the high-fat diet increased significantly more than that of mice on the control diet (25.8 +/- 0.4 v 21.3 +/- 0.2 g, P < .001). Already after 1 week on the high-fat diet, a significant hyperglycemia accompanied by hyperinsulinemia had evolved, indicative of insulin resistance. After 12 weeks, plasma glucose levels for high-fat diet-treated mice were 7.5 +/- 0.1 mmol/L, versus 6.5 +/- 0.1 mmol/L in controls (P < .001); corresponding values for plasma insulin were 248 +/- 17 and 104 +/- 7 pmol/L, respectively (P < .001). Mice given a high-fat diet also had elevated levels of total cholesterol, triglycerides, and free fatty acids (FFAs) compared with controls. After 4, 8, and 12 weeks, glucose (2.8, 8.3, or 16.7 mmol/kg) or the cholinergic agonist carbachol (0.16 or 0.53 mu mol/kg) was injected intraperitoneally. The insulinotropic response to glucose was not different between the two groups after 4 or 8 weeks, whereas after 12 weeks, glucose-induced insulin secretion was markedly impaired in high-fat diet-treated mice (P < .001). In contrast, after 8 and 12 weeks on a high-fat diet,carbachol-stimulated insulin secretion was potentiated (P < .01), whereas carbachol-stimulated glucagon secretion was not significantly altered. Furthermore, after 12 weeks on the high-fat diet, insulin secretion from isolated islets was impaired at glucose levels of 8.3, 11.1, and 16.7 mmol/L (P less than or equal to .05). Moreover, islet morphology as examined by immunocytochemistry using insulin antibodies and islet innervation, as revealed by immunostaining bf tyrosine hydroxylase (TH), neuropeptide Y (NPY), galanin, vasoactive intestinal polypeptide (VIP), and substance P (SP) were unaffected by the high-fat diet for 12 weeks. However, quantitative in situ hybridization showed a 3.5-fold upregulation of insulin gene expression in response to the high-fat diet (P < .001) despite unaltered B-cell mass and pancreatic insulin content. We conclude that as little as 1 week of treatment with a high-fat diet induces insulin resistance in C57BL/6J mice. This is accompanied later by hyperlipemia, potentiated carbachol-stimulated insulin secretion, and increased insulin gene expression but impaired glucose-stimulated insulin secretion. We suggest that after several weeks' duration, insulin resistance is accompanied by enhanced islet sensitivity to cholinergic activation and exaggerated insulin gene expression, whereas the failing islet sensitivity to glucose represents decompensation. Copyright (C) 1997 by W.B. Saunders Company