Leadership Sinai Centre for Diabetes, Mount Sinai Hospital, Toronto, Ontario, Canada.
Division of Endocrinology, University of Toronto, Toronto, Ontario, Canada.
Diabetes Care. 2024 Nov 1;47(11):2017-2023. doi: 10.2337/dc24-1375.
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.
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.
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.
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.
减轻未被识别的糖毒性，从而恢复β细胞功能，可能会放大药物治疗的降血糖作用，并有助于解释 2 型糖尿病（T2D）患者之间观察到的不同治疗反应。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）可改善早期 T2D 中的糖毒性和β细胞功能。因此，为了寻找是否存在一个空腹血糖基线阈值，高于该阈值，IIT 后β细胞功能和血糖的改善会被放大，我们试图确定是否存在这种情况。
108 例 T2D 成人患者（平均病程 1.8±1.4 年）接受为期 3 周的 IIT（甘精胰岛素、赖脯胰岛素）治疗。IIT 前后进行口服葡萄糖耐量试验，通过胰岛素分泌敏感指数-2 和胰岛素原指数/HOMA-胰岛素抵抗评估β细胞功能。对于空腹血糖水平从 6.0 到 10.5mmol/L 的每个水平，我们构建了模型，以比较空腹血糖处于或高于所指示的血糖水平的患者与低于该水平的患者的 IIT 诱导的β细胞功能变化百分比之间的差异。
空腹血糖与β细胞功能变化差异之间的关系是非线性的。相反，这种关系最符合三次回归模型，空腹血糖为 9.3mmol/L 时有拐点（放大）。此外，空腹血糖为 9.3mmol/L 还确定了空腹血糖和 2 小时血糖分别非线性降低时的拐点，这两个拐点都被放大了。
短期 IIT 后β细胞功能和血糖的相应改善在空腹血糖超过定义阈值的患者中被放大，这与糖毒性的逆转一致。
