incretins and Kidney-Failure--Chronic

Topics: Diabetes Mellitus, Type 2; Diabetic Nephropathies; Disease Progression; Endothelin A Receptor Antagonists; Humans; Incretins; Kidney Failure, Chronic; Renal Insufficiency, Chronic; Sodium-Glucose Transporter 2 Inhibitors

The insulin-stimulating and glucagon-regulating effects of the 2 incretin hormones, glucagon-like peptide 1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), contribute to maintain normal glucose homeostasis. Impaired glucose tolerance occurs with high prevalence among patients with end-stage renal disease (ESRD).. To evaluate the effect of the incretin hormones on endocrine pancreatic function in patients with ESRD.. Twelve ESRD patients on chronic hemodialysis and 12 matched healthy controls, all with normal oral glucose tolerance test, were included. On 3 separate days, a 2-hour euglycemic clamp followed by a 2-hour hyperglycemic clamp (3 mM above fasting level) was performed with concomitant infusion of GLP-1 (1 pmol/kg/min), GIP (2 pmol/kg/min), or saline administered in a randomized, double-blinded fashion. A 30% lower infusion rate was used in the ESRD group to obtain comparable incretin hormone plasma levels.. During clamps, comparable plasma glucose and intact incretin hormone concentrations were achieved. The effect of GLP-1 to increase insulin concentrations relative to placebo levels tended to be lower during euglycemia in ESRD and was significantly reduced during hyperglycemia (50 [8-72]%, P = 0.03). Similarly, the effect of GIP relative to placebo levels tended to be lower during euglycemia in ESRD and was significantly reduced during hyperglycemia (34 [13-50]%, P = 0.005). Glucagon was suppressed in both groups, with controls reaching lower concentrations than ESRD patients.. The effect of incretin hormones to increase insulin release is reduced in ESRD, which, together with elevated glucagon levels, could contribute to the high prevalence of impaired glucose tolerance among ESRD patients.

Topics: Adult; Denmark; Double-Blind Method; Female; Glucagon; Glucagon-Like Peptide 1; Glucose Clamp Technique; Glucose Tolerance Test; Humans; Incretins; Insulin; Insulin Secretion; Islets of Langerhans; Kidney Failure, Chronic; Male; Middle Aged; Renal Dialysis

Patients with end-stage renal disease (ESRD) have glucometabolic disturbances resulting in a high prevalence of prediabetes. The underlying pathophysiology remains unclear, but may prove important for the strategies employed to prevent progression to overt diabetes. Meal-induced release of the insulinotropic gut-derived incretin hormones and pancreatic hormones play a critical role in the maintenance of a normal postprandial glucose tolerance.. We studied patients with ESRD and either normal (n = 10) or impaired (n = 10) glucose tolerance, and control subjects (n = 11). Plasma concentrations of glucose, insulin, glucagon, glucagon-like peptide-1 (GLP-1), glucose-dependent insulinotropic polypeptide (GIP) and paracetamol were measured repeatedly during a standardized 4-h liquid meal including 1.5 g paracetamol (added for evaluation of gastric emptying).. Fasting glucose and postprandial glucose responses were comparable between groups (P > 0.082). Patients with ESRD exhibited higher fasting levels of GIP and glucagon compared with controls (P < 0.001). Baseline-corrected GLP-1 and glucagon responses were enhanced (P < 0.002), baseline-corrected insulin responses and insulin excursions were reduced (P < 0.035), and paracetamol excursions were delayed (P < 0.024) in patients with ESRD compared with controls. None of the variables differed between the two ESRD subgroups.. Non-diabetic patients with ESRD were characterized by reduced postprandial insulin responses despite increased secretion of the insulinotropic incretin hormone GLP-1. Fasting levels and baseline-corrected responses of glucagon were elevated and gastric emptying was delayed in the ESRD patients. These perturbations seem to be caused by uraemia per se and may contribute to the disturbed glucose metabolism in ESRD patients.

Topics: Adult; Blood Glucose; Female; Gastric Emptying; Gastric Inhibitory Polypeptide; Glucagon; Glucagon-Like Peptide 1; Humans; Incretins; Insulin; Kidney Failure, Chronic; Male; Middle Aged; Pancreatic Hormones; Postprandial Period

Nondiabetic patients with end-stage renal disease (ESRD) have disturbed glucose metabolism, the underlying pathophysiology of which is unclear. To help elucidate this, we studied patients with ESRD and either normal or impaired glucose tolerance (10 each NGT or IGT, respectively) and 11 controls using an oral glucose tolerance test and an isoglycemic intravenous glucose infusion on separate days. Plasma glucose, insulin, glucagon, and incretin hormones were measured repeatedly, and gastrointestinal-mediated glucose disposal (GIGD) based on glucose amounts utilized, and incretin effect based on incremental insulin responses, were calculated. The GIGD was significantly reduced in both ESRD groups compared with controls. Incretin effects were 69% (controls), 55% (ESRD with NGT), and 41% (ESRD with IGT), with a significant difference between controls and ESRDs with IGT. Fasting concentrations of glucagon and incretin hormones were significantly increased in patients with ESRD. Glucagon suppression was significantly impaired in both groups with ESRD compared with controls, while the baseline-corrected incretin hormone responses were unaltered between groups. Thus, patients with ESRD had reduced GIGD, a diminished incretin effect in those with IGT, and severe fasting hyperglucagonemia that seemed irrepressible in response to glucose stimuli. These factors may contribute to disturbed glucose metabolism in ESRD.

Topics: Adult; Analysis of Variance; Area Under Curve; Biomarkers; Blood Glucose; Case-Control Studies; Fasting; Female; Gastric Inhibitory Polypeptide; Gastrointestinal Tract; Glucagon; Glucagon-Like Peptide 1; Glucose Metabolism Disorders; Glucose Tolerance Test; Humans; Incretins; Insulin; Kidney Failure, Chronic; Linear Models; Male; Middle Aged; Time Factors

We herein report two cases of pancreatitis associated with incretin-based therapies in end-stage renal disease (ESRD) patients undergoing dialysis. A 75-year-old woman with a history of liraglutide use and a 68-year-old man with a history of vildagliptin use both presented with nausea. They showed elevated levels of pancreatic enzymes and pancreatic tail swelling on CT. Their symptoms improved after discontinuing the drugs. In the absence of any obvious secondary causes of pancreatitis, we believe that the pancreatitis observed in these cases was associated with the incretin-based therapies. Few reports have been published on the safety and efficacy of incretin-based therapies in ESRD patients, and it remains uncertain whether the changes in the pancreas observed in the present cases are characteristic of ESRD patients.

Topics: Adamantane; Aged; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Female; Glucagon-Like Peptide 1; Humans; Incretins; Kidney Failure, Chronic; Liraglutide; Magnetic Resonance Imaging; Male; Nitriles; Pancreatitis; Pyrrolidines; Renal Dialysis; Tomography, X-Ray Computed; Vildagliptin