Impaired incretin homeostasis in non-diabetic moderate-severe CKD

Abstract

AbstractBackgroundIncretins are regulators of insulin secretion and glucose homeostasis that are metabolized by dipeptidyl peptidase-4 (DPP-4). Moderate-severe CKD may modify incretin release, metabolism, or response.MethodsWe performed 2-hour oral glucose tolerance testing (OGTT) in 59 people with non-diabetic CKD (eGFR<60 ml/min per 1.73 m2) and 39 matched controls. We measured total (tAUC) and incremental (iAUC) area under the curve 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.ResultsMean eGFR was 38 ±13 and 89 ±17ml/min per 1.73 m2in CKD and controls. GLP-1 iAUC and GIP iAUC were higher in CKD than controls with a mean of 1531 ±1452 versus 1364 ±1484 pMxmin, and 62370 ±33453 versus 42365 ±25061 pgxmin/ml, respectively. After adjustment, CKD was associated with 15271 pMxmin/ml greater GIP iAUC (95% CI 387, 30154) compared to controls. Adjustment for covariates attenuated associations of CKD with higher GLP-1 iAUC (adjusted difference, 122, 95% CI -619, 864). Plasma glucagon levels were higher at 30 minutes (mean difference, 1.6, 95% CI 0.3, 2.8 mg/dl) and 120 minutes (mean difference, 0.84, 95% CI 0.2, 1.5 mg/dl) in CKD compared to controls. There were no differences in insulin levels or plasma DPP-4 activity or levels between groups.ConclusionIncretin response to oral glucose is preserved or augmented in moderate-severe CKD, without apparent differences in circulating DPP-4 concentration or activity. However, neither insulin secretion nor glucagon suppression are enhanced.Significance statementCKD is associated with metabolic and physiological disturbances including disturbed glucose and insulin homeostasis. Incretin hormones are potent regulators of insulin secretion and glucose metabolism; however, determinants and potential consequence of incretin response in CKD are incompletely understood. This study revealed that total incretin levels and incretin response during oral glucose tolerance testing (OGTT) were significantly higher among patients with moderate-severe non-diabetic CKD compared to healthy. Unlike in healthy individuals, increased incretin response was not correlated with insulin and C-peptide response to OGTT in CKD. These differences coincided with persistently greater glucagon levels in response to physiological stimuli in CKD. Disruption in the incretin system and glucagon dynamics may contribute to metabolic disturbances in moderate-severe CKD.Visual abstract