PDF(Pubmed)
Abstract：
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 ± 2.1 years (mean ± SD), 68% female, body mass index (BMI) 40.1 ± 7.9 kg/m2, duration of diagnosis 1.8 ± 1.3 years-were randomized to metformin alone (Met) or metformin + liraglutide (Lira) (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 2-hour oral glucose tolerance test.
RESULTS: At baseline, gluconeogenesis, glucose production, and fasting and 2-hour glucose were comparable in both groups, though Met + Lira had higher hemoglobin A1C. Met + Lira had a greater decrease from baseline in fasting glucose (-2.0 ± 1.3 vs -0.6 ± 0.9 mmol/L, P = .008) and a greater increase in sigma (0.72 ± 0.68 vs -0.05 ± 0.71, P = .03). The change in fractional gluconeogenesis was similar between groups (Met + Lira: -0.36 ± 9.4 vs Met: 0.04 ± 12.3%, P = .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 = .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.
METHODS: In this parallel randomized clinical trial, 22 youth with Y-T2D-age 15.3 ± 2.1 years (mean ± SD), 68% female, body mass index (BMI) 40.1 ± 7.9 kg/m2, duration of diagnosis 1.8 ± 1.3 years-were randomized to metformin alone (Met) or metformin + liraglutide (Lira) (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 2-hour oral glucose tolerance test.
RESULTS: At baseline, gluconeogenesis, glucose production, and fasting and 2-hour glucose were comparable in both groups, though Met + Lira had higher hemoglobin A1C. Met + Lira had a greater decrease from baseline in fasting glucose (-2.0 ± 1.3 vs -0.6 ± 0.9 mmol/L, P = .008) and a greater increase in sigma (0.72 ± 0.68 vs -0.05 ± 0.71, P = .03). The change in fractional gluconeogenesis was similar between groups (Met + Lira: -0.36 ± 9.4 vs Met: 0.04 ± 12.3%, P = .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 = .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.
摘要：
目的：糖异生率升高是青年型2型糖尿病（Y-T2D）的早期致病特征，但是有针对性的一线疗法并不理想，特别是在非洲裔美国人（AA）青年。我们通过测量AAY-T2D治疗后糖异生速率和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青年：年龄15.3±2.1y（平均值±SD），68%的女性，BMI40.1±7.9kg/m2，诊断持续时间1.8±1.3y被随机分为单独二甲双胍（Met）或二甲双胍+利拉鲁肽（Met+Lira），并在12周之前和之后进行评估。稳定的同位素示踪剂用于在过夜禁食和连续进餐后测量糖异生[2H2O]和葡萄糖的产生[6,6-2H2]葡萄糖。在频繁采样的2h-OGTT期间评估了β细胞功能（sigma）和全身胰岛素敏感性（mSI）。
结果：在基线时，糖异生,葡萄糖生产，空腹血糖和2小时血糖在两组中具有可比性，尽管Met+Lira的HbA1c较高。MetLira的空腹血糖比基线下降更大（-2.0±1.3vs.-0.6±0.9mmol/L,P=0.008）和更大的sigma增加（0.72±0.68vs.-0.05±0.71，P=0.03）。各组之间糖异生分数的变化相似（MetLira：-0.36±9.4vs.Met:0.04±12.3%,P=0.9），餐时糖异生或mSI没有变化。两组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可改善血糖,但不能抑制高糖异生率.需要能够增强β细胞功能并靶向Y-T2D中糖异生速率升高的新疗法。
方法：在这项平行随机临床试验中，22名Y-T2D青年：年龄15.3±2.1y（平均值±SD），68%的女性，BMI40.1±7.9kg/m2，诊断持续时间1.8±1.3y被随机分为单独二甲双胍（Met）或二甲双胍+利拉鲁肽（Met+Lira），并在12周之前和之后进行评估。稳定的同位素示踪剂用于在过夜禁食和连续进餐后测量糖异生[2H2O]和葡萄糖的产生[6,6-2H2]葡萄糖。在频繁采样的2h-OGTT期间评估了β细胞功能（sigma）和全身胰岛素敏感性（mSI）。
结果：在基线时，糖异生,葡萄糖生产，空腹血糖和2小时血糖在两组中具有可比性，尽管Met+Lira的HbA1c较高。MetLira的空腹血糖比基线下降更大（-2.0±1.3vs.-0.6±0.9mmol/L,P=0.008）和更大的sigma增加（0.72±0.68vs.-0.05±0.71，P=0.03）。各组之间糖异生分数的变化相似（MetLira：-0.36±9.4vs.Met:0.04±12.3%,P=0.9），餐时糖异生或mSI没有变化。两组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可改善血糖,但不能抑制高糖异生率.需要能够增强β细胞功能并靶向Y-T2D中糖异生速率升高的新疗法。
