Insulin resistance (IR) is predictive for type 2 diabetes and associated with various metabolic abnormalities in fasting conditions. However, limited data are available on how IR affects metabolic responses in a non-fasting setting, yet this is the state people are mostly exposed to during waking hours in the modern society. Here, we aim to comprehensively characterise the metabolic changes in response to an oral glucose test (OGTT) and assess the associations of these changes with IR. Blood samples were obtained at 0 (fasting baseline, right before glucose ingestion), 30, 60, and 120 min during the OGTT. Seventy-eight metabolic measures were analysed at each time point for a discovery cohort of 4745 middle-aged Finnish individuals and a replication cohort of 595 senior Finnish participants. We assessed the metabolic changes in response to glucose ingestion (percentage change in relative to fasting baseline) across the four time points and further compared the response profile between five groups with different levels of IR and glucose intolerance. Further, the differences were tested for covariate adjustment, including gender, body mass index, systolic blood pressure, fasting, and 2-h glucose levels. The groups were defined as insulin sensitive with normal glucose (IS-NGT), insulin resistant with normal glucose (IR-NGT), impaired fasting glucose (IFG), impaired glucose tolerance (IGT), and new diabetes (NDM). IS-NGT and IR-NGT were defined as the first and fourth quartile of fasting insulin in NGT individuals. Glucose ingestion induced multiple metabolic responses, including increased glycolysis intermediates and decreased branched-chain amino acids, ketone bodies, glycerol, and triglycerides. The IR-NGT subgroup showed smaller responses for these measures (mean + 23%, interquartile 9–34% at 120 min) compared to IS-NGT (34%, 23–44%, P < 0.0006 for difference, corrected for multiple testing). Notably, the three groups with glucose abnormality (IFG, IGT, and NDM) showed similar metabolic dysregulations as those of IR-NGT. The difference between the IS-NGT and the other subgroups was largely explained by fasting insulin, but not fasting or 2 h glucose. The findings were consistent after covariate adjustment and between the discovery and replication cohort. Insulin-resistant non-diabetic individuals are exposed to a similar adverse postprandial metabolic milieu, and analogous cardiometabolic risk, as those with type 2 diabetes. The wide range of metabolic abnormalities associated with IR highlights the necessity of diabetes diagnostics and clinical care beyond glucose management.

中文翻译：

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5340 人口服葡萄糖耐量试验中的胰岛素抵抗和全身代谢变化：一项介入性研究

胰岛素抵抗 (IR) 可预测 2 型糖尿病，并与禁食条件下的各种代谢异常相关。然而，关于 IR 如何在非禁食环境中影响代谢反应的数据有限，但这是现代社会中人们在清醒时间最常接触到的状态。在这里，我们的目标是全面表征响应口服葡萄糖测试 (OGTT) 的代谢变化，并评估这些变化与 IR 的关联。在 OGTT 期间的 0（禁食基线，葡萄糖摄入前）、30、60 和 120 分钟获得血样。针对 4745 名芬兰中年个体的发现队列和 595 名芬兰高级参与者的复制队列，在每个时间点分析了 78 项代谢测量。我们评估了四个时间点响应葡萄糖摄入的代谢变化（相对于空腹基线的百分比变化），并进一步比较了 IR 和葡萄糖不耐受水平不同的五组之间的反应概况。此外，还对这些差异进行了协变量调整测试，包括性别、体重指数、收缩压、空腹和 2 小时血糖水平。这些组被定义为血糖正常的胰岛素敏感组（IS-NGT）、血糖正常的胰岛素抵抗组（IR-NGT）、空腹血糖受损（IFG）、糖耐量受损（IGT）和新发糖尿病（NDM）。IS-NGT 和 IR-NGT 被定义为 NGT 个体空腹胰岛素的第一和第四四分位数。葡萄糖摄入诱导多种代谢反应，包括增加的糖酵解中间体和减少的支链氨基酸、酮体、甘油和甘油三酯。与 IS-NGT 相比，IR-NGT 亚组对这些测量的反应较小（平均值 + 23%，四分位间距 9-34%）（34%，23-44%，差异 P < 0.0006，针对多次测试进行校正） ）。值得注意的是，三组葡萄糖异常（IFG、IGT 和 NDM）表现出与 IR-NGT 相似的代谢失调。IS-NGT 和其他亚组之间的差异主要由空腹胰岛素解释，而不是空腹或 2 小时葡萄糖。在协变量调整后以及发现队列和复制队列之间的发现是一致的。胰岛素抵抗的非糖尿病个体暴露于类似的不利餐后代谢环境和类似的心脏代谢风险，与那些患有 2 型糖尿病的人一样。与 IR 相关的广泛代谢异常突出了糖尿病诊断和临床护理超越血糖管理的必要性。