Computational Medicine, Institute of Clinical Medicine, University of Oulu, Oulu, Finland.
Diabetes Care. 2012 Aug;35(8):1749-56. doi: 10.2337/dc11-1838. Epub 2012 May 4.
Metabolite predictors of deteriorating glucose tolerance may elucidate the pathogenesis of type 2 diabetes. We investigated associations of circulating metabolites from high-throughput profiling with fasting and postload glycemia cross-sectionally and prospectively on the population level.
Oral glucose tolerance was assessed in two Finnish, population-based studies consisting of 1,873 individuals (mean age 52 years, 58% women) and reexamined after 6.5 years for 618 individuals in one of the cohorts. Metabolites were quantified by nuclear magnetic resonance spectroscopy from fasting serum samples. Associations were studied by linear regression models adjusted for established risk factors.
Nineteen circulating metabolites, including amino acids, gluconeogenic substrates, and fatty acid measures, were cross-sectionally associated with fasting and/or postload glucose (P < 0.001). Among these metabolic intermediates, branched-chain amino acids, phenylalanine, and α1-acid glycoprotein were predictors of both fasting and 2-h glucose at 6.5-year follow-up (P < 0.05), whereas alanine, lactate, pyruvate, and tyrosine were uniquely associated with 6.5-year postload glucose (P = 0.003-0.04). None of the fatty acid measures were prospectively associated with glycemia. Changes in fatty acid concentrations were associated with changes in fasting and postload glycemia during follow-up; however, changes in branched-chain amino acids did not follow glucose dynamics, and gluconeogenic substrates only paralleled changes in fasting glucose.
Alterations in branched-chain and aromatic amino acid metabolism precede hyperglycemia in the general population. Further, alanine, lactate, and pyruvate were predictive of postchallenge glucose exclusively. These gluconeogenic precursors are potential markers of long-term impaired insulin sensitivity that may relate to attenuated glucose tolerance later in life.
恶化的葡萄糖耐量的代谢物预测因子可能阐明 2 型糖尿病的发病机制。我们研究了来自高通量分析的循环代谢物与空腹和餐后血糖的横断面和前瞻性人群水平的关联。
在两项芬兰人群为基础的研究中评估了口服葡萄糖耐量，其中包括 1873 名个体（平均年龄 52 岁，58%为女性），并在其中一个队列中对 618 名个体进行了 6.5 年的复查。通过核磁共振波谱法从空腹血清样本中定量测定代谢物。通过调整既定风险因素的线性回归模型研究了关联。
19 种循环代谢物，包括氨基酸、糖异生底物和脂肪酸测量值，与空腹和/或餐后血糖呈横断面相关（P < 0.001）。在这些代谢中间产物中，支链氨基酸、苯丙氨酸和α1-酸性糖蛋白是空腹和 6.5 年随访时 2 小时血糖的预测因子（P < 0.05），而丙氨酸、乳酸、丙酮酸和酪氨酸则与 6.5 年餐后血糖唯一相关（P = 0.003-0.04）。脂肪酸测量值均与血糖无前瞻性关联。随访期间，脂肪酸浓度的变化与空腹和餐后血糖的变化相关；然而，支链氨基酸的变化并不遵循葡萄糖动力学，而糖异生底物仅与空腹血糖的变化平行。
在一般人群中，支链和芳香族氨基酸代谢的改变先于高血糖。此外，丙氨酸、乳酸和丙酮酸仅能预测餐后血糖。这些糖异生前体可能是长期胰岛素敏感性受损的潜在标志物，可能与以后生活中糖耐量受损有关。
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