OBJECTIVE Alleviation of unrecognized glucotoxicity, with resultant recovery of β-cell function, could amplify the glucose-lowering effect of pharmacotherapy and contribute to the variable therapeutic response observed among patients with type 2 diabetes (T2D). However, clinical evidence supporting this concept is lacking. Short-term intensive insulin therapy (IIT) can ameliorate glucotoxicity and improve β-cell function in early T2D. Thus, for evidence of recovery of glucotoxicity-associated β-cell dysfunction, we sought to determine whether there exists a baseline fasting glucose threshold above which the post-IIT improvement in both β-cell function and glycemia is amplified. RESEARCH DESIGN AND METHODS IIT (glargine, lispro) was administered for 3 weeks to 108 adults with T2D (mean duration 1.8 ± 1.4 years). Oral glucose tolerance tests before and after IIT enabled assessment of β-cell function by Insulin Secretion-Sensitivity Index-2 and insulinogenic index/HOMA-insulin resistance. For each level of baseline fasting glycemia from 6.0 to 10.5 mmol/L, we modeled the difference in IIT-induced percentage change in β-cell function between those at/above the indicated glucose level and those below it. RESULTS The relationship between baseline fasting glucose and the differential change in β-cell function was nonlinear. Instead, this relationship was best fit by a cubic regression model with inflection (amplification) at fasting glucose at 9.3 mmol/L. Moreover, baseline fasting glucose at 9.3 mmol/L also identified the inflection point at which nonlinear reductions in fasting glucose and 2-h glucose, respectively, were both amplified. CONCLUSIONS The respective improvements in β-cell function and glycemia in response to short-term IIT are amplified in those in whom baseline fasting glucose exceeds a defined threshold, consistent with reversal of glucotoxicity.

中文翻译：

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在早期 2 型糖尿病中，超过该阈值，胰岛素治疗后β细胞功能和血糖的改善被放大：糖毒性的逆转


目的 减轻未被识别的糖毒性，从而恢复β细胞功能，可以放大药物治疗的降糖作用，并导致在 2 型糖尿病 （T2D） 患者中观察到的可变治疗反应。然而，缺乏支持这一概念的临床证据。短期强化胰岛素治疗 （IIT） 可以改善 T2D 早期的糖毒性并改善 β 细胞功能。因此，为了获得糖毒性相关 β 细胞功能障碍恢复的证据，我们试图确定是否存在基线空腹血糖阈值，超过该阈值，IIT 后β细胞功能和血糖的改善被放大。研究设计和方法 对 108 名患有 T2D 的成人患者 （平均持续时间 1.8 ± 1.4 年） 进行了为期 3 周的 IIT （甘精胰岛素、赖脯胰岛素）。IIT 前后的口服葡萄糖耐量试验能够通过胰岛素分泌敏感性指数 2 和胰岛素生成指数/HOMA-胰岛素抵抗评估β细胞功能。对于从 6.0 到 10.5 mmol/L 的每个基线空腹血糖水平，我们模拟了 IIT 诱导的β细胞功能百分比变化在达到/高于指定葡萄糖水平的人与低于指定葡萄糖水平的人之间的差异。结果 基线空腹血糖与 β 细胞功能的差异变化之间的关系是非线性的。相反，这种关系最好通过三次回归模型进行拟合，该模型在 9.3 mmol/L 的空腹血糖时发生拐点（扩增）。此外，基线空腹血糖为 9.3 mmol/L 也确定了空腹血糖和 2 小时血糖非线性降低分别被放大的拐点。 结论 在基线空腹血糖超过规定阈值的患者中，响应短期 IIT 的 β 细胞功能和血糖的相应改善被放大，与糖毒性的逆转一致。