Impaired incretin homeostasis in non-diabetic moderate to severe chronic kidney disease

Key Points 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. Background Incretins are regulators of insulin secretion and glucose homeostasis metabolized by dipeptidyl peptidase-4 (DPP-4). CKD may modify incretin release, metabolism, or response. Methods We performed 2-hour oral glucose tolerance testing in 59 people with nondiabetic CKD (eGFR <60 ml/min per 1.73 m 2 ) 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. Results Mean (SD) eGFR was 38±13 and 89±17 ml/min per 1.73 m 2 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. Conclusions 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.