Ahmadi Armin, Gamboa Jorge, Norman Jennifer E, Enkhmaa Bamba, Tucker Madelynn, Bennett Brian J, Zelnick Leila R, Fan Sili, Berglund Lars F, Ikizler Talat Alp, de Boer Ian H, Cummings Bethany P, Roshanravan Baback
Division of Nephrology, Department of Internal Medicine, University of California, Davis, California.
Division of Clinical Pharmacology, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee.
Clin J Am Soc Nephrol. 2025 Jan 1;20(1):12-22. doi: 10.2215/CJN.0000000000000566. Epub 2024 Oct 9.
Total incretin levels and incretin response during oral glucose tolerance testing were significantly higher among patients with moderate-to-severe nondiabetic patients with CKD compared with healthy people. Unlike in healthy individuals, increased incretin response was not correlated with insulin response and coincided with persistently greater glucagon levels to oral glucose tolerance testing in CKD. Disruption in the incretin system and glucagon dynamics may contribute to metabolic complications in moderate-to-severe CKD.
Incretins are regulators of insulin secretion and glucose homeostasis metabolized by dipeptidyl peptidase-4 (DPP-4). CKD may modify incretin release, metabolism, or response.
We performed 2-hour oral glucose tolerance testing in 59 people with nondiabetic CKD (eGFR <60 ml/min per 1.73 m) and 39 matched controls. We measured total area under the curve and incremental area under the curve (iAUC) of plasma total glucagon-like peptide-1 (GLP-1) and total glucose-dependent insulinotropic polypeptide (GIP). Fasting DPP-4 levels and activity were measured. Linear regression was used to adjust for demographic, body composition, and lifestyle factors.
Mean (SD) eGFR was 38±13 and 89±17 ml/min per 1.73 m in patients with CKD and controls, respectively. GLP-1 total area under the curve and GIP iAUC were higher in patients with CKD than controls with a mean of 1531±1452 versus 1364±1484 pM×min and 62,370±33,453 versus 42,365±25,061 pg×min/ml, respectively. After adjustment, CKD was associated with 15,271 pM×min/ml greater GIP iAUC (95% confidence intervals [CIs], 387 to 30,154) compared with controls. Adjustment for covariates attenuated associations of CKD with higher GLP-1 iAUC (adjusted difference, 122; 95% CI, −619 to 864). Plasma glucagon levels were higher at 30 minutes (mean difference, 1.6; 95% CI, 0.3 to 2.8 mg/dl) and 120 minutes (mean difference, 0.84; 95% CI, 0.2 to 1.5 mg/dl) in patients with CKD compared with controls. There were no differences in insulin levels or plasma DPP-4 activity or levels between groups.
Overall, incretin response to oral glucose is preserved or augmented in moderate-to-severe CKD, without apparent differences in circulating DPP-4 concentration or activity. However, neither insulin secretion nor glucagon suppression is enhanced.
与健康人相比，中重度非糖尿病慢性肾脏病（CKD）患者口服葡萄糖耐量试验期间的肠促胰岛素总水平和肠促胰岛素反应显著更高。与健康个体不同，CKD患者肠促胰岛素反应增加与胰岛素反应无关，且与口服葡萄糖耐量试验期间持续更高的胰高血糖素水平同时出现。肠促胰岛素系统和胰高血糖素动态变化的破坏可能导致中重度CKD的代谢并发症。
肠促胰岛素是由二肽基肽酶-4（DPP-4）代谢的胰岛素分泌和葡萄糖稳态调节剂。CKD可能会改变肠促胰岛素的释放、代谢或反应。
我们对59例非糖尿病CKD患者（估算肾小球滤过率[eGFR]<60 ml/（min·1.73 m²））和39例匹配的对照者进行了2小时口服葡萄糖耐量试验。我们测量了血浆总胰高血糖素样肽-1（GLP-1）和总葡萄糖依赖性促胰岛素多肽（GIP）的曲线下总面积和增量曲线下面积（iAUC）。测量了空腹DPP-4水平和活性。使用线性回归来校正人口统计学、身体组成和生活方式因素。
CKD患者和对照组的平均（标准差）eGFR分别为38±13和89±17 ml/（min·1.73 m²）。CKD患者的GLP-1曲线下总面积和GIP iAUC高于对照组，平均值分别为1531±1452与1364±1484 pM·min和62370±33453与42365±25061 pg·min/ml。校正后，与对照组相比，CKD与GIP iAUC增加15271 pM·min/ml相关（95%置信区间[CI]，387至30154）。协变量校正减弱了CKD与更高GLP-1 iAUC的相关性（校正差异，122；95%CI，-619至864）。与对照组相比，CKD患者在30分钟时血浆胰高血糖素水平更高（平均差异，1.6；95%CI，0.3至2.8 mg/dl），在120分钟时更高（平均差异，0.84；95%CI，0.2至1.5 mg/dl）。两组之间胰岛素水平、血浆DPP-4活性或水平无差异。
总体而言，中重度CKD患者对口服葡萄糖的肠促胰岛素反应得以保留或增强，循环DPP-4浓度或活性无明显差异。然而，胰岛素分泌和胰高血糖素抑制均未增强。
