Exenatide (Exendin-4) improves insulin sensitivity and β-cell mass in insulin-resistant obese fa/fa Zucker rats independent of glycemia and body weight
Exenatide (Exendin-4) improves insulin sensitivity and β-cell mass in insulin-resistant obese fa/fa Zucker rats independent of glycemia and body weight
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DOI：
10.1210/en.2004-1349
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发表时间：
2005-04-01
期刊：
影响因子：
4.8
通讯作者：
Young, AA
中科院分区：
文献类型：
--
作者：
Gedulin, BR;Nikoulina, SE;Young, AA
在非糖尿病、胰岛素抵抗的肥胖fa/ fa Zucker大鼠中，研究了肠促胰岛素模拟物艾塞那肽（exendin- 4）对代谢参数、胰岛素敏感性和β细胞质量的影响。治疗6周后，随意喂养的艾塞那肽处理大鼠（EX）和配对喂养的对照大鼠（PF）的食物摄入量、体重、血红蛋白（1c） （HbA(1c)）和空腹血浆葡萄糖、胰岛素和脂质浓度相当。与自由喂养对照（CON）大鼠相比，EX和PF大鼠的进食量和体重增加同时减少（P < 0.001）。与对照组大鼠相比，EX和PF大鼠在疾病模型正常进展过程中出现的HbA（1c）和空腹血浆胰岛素浓度的升高明显降低（P < 0.001）。胰岛素敏感性指数（ISI，葡萄糖输注率对血浆胰岛素浓度的比值）在高胰岛素正糖钳夹期间，EX大鼠比CON大鼠高224% (P < 0.001)， EX大鼠比PF大鼠高61% （P < 0.004）。尽管EX和PF动物之间的HbA（1c）、空腹血糖、空腹胰岛素、总胆固醇、高密度脂蛋白和每日食物消耗具有可比性，但后者的差异仍然存在。在没有艾塞那肽的情况下，β细胞质量与ISI呈双曲线相关（β细胞质量* ISI恒定）。与处置指数类似，EX大鼠的β细胞质量* ISI积比PF大鼠高63% （P < 0.05）。因此，艾塞那肽增加β细胞质量的程度比预期的胰岛素抵抗动物更大，这表明对肥胖fa/ fa大鼠的胰岛新生有直接的营养作用，而不依赖于体重和血糖。
The effects of the incretin mimetic exenatide ( exendin- 4) on metabolic parameters, insulin sensitivity, and beta- cell mass were examined in nondiabetic, insulin- resistant obese fa/ fa Zucker rats. After 6 wk of treatment, ad libitum- fed exenatide-treated ( EX) and pair- fed vehicle control ( PF) rats had comparable food intake, body weight, hemoglobinA(1c) ( HbA(1c)), and fasting plasma concentrations of glucose, insulin, and lipids. Concurrent decreases in food intake and weight gain were observed in EX and PF rats, compared with ad libitum- fed vehicle control ( CON) rats ( P < 0.001). The increases in HbA(1c) and fasting plasma insulin concentrations that occur during the normal progression of this disease model were significantly reduced in EX and PF rats, compared with CON rats ( P < 0.001). The insulin sensitivity index ( ISI; glucose infusion rate to plasma insulin concentration) measured during a hyperinsulinemic euglycemic clamp was 224% higher in EX rats than CON rats ( P < 0.001) and 61% higher in EX rats than PF rats ( P < 0.004). The latter difference was despite comparable HbA(1c), fasting glucose, fasting insulin, total cholesterol, high-density lipoprotein, and daily food consumption between EX and PF animals. In the absence of exenatide, beta- cell mass was hyperbolically related to ISI ( beta- cell mass * ISI was constant). Analogous to the disposition index, the beta- cell mass * ISI product was 63% greater in EX than PF rats ( P < 0.05). Thus, exenatide increased beta- cell mass to a greater extent than would be expected in animals of comparable insulin resistance, suggesting a direct trophic effect on islet neogenesis in obese fa/ fa rats independent of body weight and glycemia.