OBJECTIVE Elevated rates of gluconeogenesis are an early pathogenic feature of youth-onset type 2 diabetes (Y-T2D), but targeted first-line therapies are suboptimal, especially in African American (AA) youth. We evaluated glucose-lowering mechanisms of metformin and liraglutide by measuring rates of gluconeogenesis and β-cell function after therapy in AA Y-T2D. METHODS In this parallel randomized clinical trial, 22 youth with Y-T2D: age 15.3±2.1y (mean±SD), 68% female, BMI 40.1±7.9kg/m2, duration of diagnosis 1.8±1.3y were randomized to metformin alone (Met) or metformin+liraglutide (Met+Lira) and evaluated before and after 12 weeks. Stable isotope tracers were used to measure gluconeogenesis [2H2O] and glucose production [6,6-2H2]glucose after an overnight fast and during a continuous meal. β-cell function (sigma) and whole-body insulin sensitivity (mSI) were assessed during a frequently sampled 2h-OGTT. RESULTS At baseline, gluconeogenesis, glucose production, and fasting and 2h glucose were comparable in both groups, though Met+Lira had higher HbA1c. Met+Lira had a greater decrease from baseline in fasting glucose (-2.0±1.3 vs. -0.6±0.9 mmol/L, P=0.008) and a greater increase in sigma (0.72±0.68 vs. -0.05±0.71, P=0.03). The change in fractional gluconeogenesis was similar between groups (Met+Lira: -0.36±9.4 vs. Met: 0.04±12.3%, P=0.9) and there were no changes in prandial gluconeogenesis or mSI. Increased glucose clearance in both groups was related to sigma (r=0.63, P=0.003) but not gluconeogenesis or mSI. CONCLUSIONS Among Y-T2D, metformin with or without liraglutide improved glycemia but did not suppress high rates of gluconeogenesis. Novel therapies that will enhance β-cell function and target the elevated rates of gluconeogenesis in Y-T2D are needed.

中文翻译：

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二甲双胍和利拉鲁肽的血糖和糖异生：青年发病 2 型糖尿病的随机试验。

目的 糖异生率升高是青年发病 2 型糖尿病 (Y-T2D) 的早期致病特征，但一线靶向治疗效果不佳，尤其是在非裔美国 (AA) 青年中。我们通过测量 AA Y-T2D 治疗后的糖异生率和 β 细胞功能来评估二甲双胍和利拉鲁肽的降糖机制。方法 在这项平行随机临床试验中，22 名 Y-T2D 青少年：年龄 15.3±2.1 岁（平均值±标准差），68% 女性，BMI 40.1±7.9kg/m2，诊断持续时间 1.8±1.3 年，被随机分配至单用二甲双胍治疗组(Met) 或二甲双胍+利拉鲁肽 (Met+Lira) 并在 12 周前后进行评估。使用稳定同位素示踪剂来测量禁食过夜和连续进餐期间的糖异生 [2H2O] 和葡萄糖生成 [6,6-2H2] 葡萄糖。在频繁采样的 2 小时-OGTT 期间评估 β 细胞功能 (sigma) 和全身胰岛素敏感性 (mSI)。结果 在基线时，两组的糖异生、葡萄糖生成以及空腹和 2 小时血糖相当，但 Met+Lira 的 HbA1c 较高。Met+Lira 的空腹血糖较基线下降幅度更大（-2.0±1.3 vs. -0.6±0.9 mmol/L，P=0.008），并且 sigma 增加幅度更大（0.72±0.68 vs. -0.05±0.71，P= 0.03）。各组之间糖异生分数的变化相似（Met+Lira：-0.36±9.4 vs. Met：0.04±12.3%，P=0.9），并且餐时糖异生或 mSI 没有变化。两组中葡萄糖清除率的增加与 sigma 有关（r=0.63，P=0.003），但与糖异生或 mSI 无关。结论 在 Y-T2D 中，二甲双胍联合或不联合利拉鲁肽均可改善血糖，但不能抑制高糖异生率。需要新的疗法来增强 β 细胞功能并针对 Y-T2D 中糖异生率升高的情况。