title: GLP-1 Cleavage Product Reverses Persistent ROS Generation After Transient Hyperglycemia by Disrupting an ROS-Generating Feedback Loop.
abstract: The assumption underlying current diabetes treatment is that lowering the level of time-averaged glucose concentrations, measured as HbA1c, prevents microvascular complications. However, 89% of variation in risk of retinopathy, microalbuminuria, or albuminuria is due to elements of glycemia not captured by mean HbA1c values. We show that transient exposure to high glucose activates a multicomponent feedback loop that causes a stable left shift of the glucose concentration-reactive oxygen species (ROS) dose-response curve. Feedback loop disruption by the GLP-1 cleavage product GLP-1(9-36)(amide) reverses the persistent left shift, thereby normalizing persistent overproduction of ROS and its pathophysiologic consequences. These data suggest that hyperglycemic spikes high enough to activate persistent ROS production during subsequent periods of normal glycemia but too brief to affect the HbA1c value are a major determinant of the 89% of diabetes complications risk not captured by HbA1c. The phenomenon and mechanism described in this study provide a basis for the development of both new biomarkers to complement HbA1c and novel therapeutic agents, including GLP-1(9-36)(amide), for the prevention and treatment of diabetes complications.
authors: Diabetes Research Center, Albert Einstein College of Medicine, Bronx, NY Department of Medicine, Albert Einstein College of Medicine, Bronx, NY.
authors: Ferdinando
authors: F
authors: Giacco
authors: Diabetes Research Center, Albert Einstein College of Medicine, Bronx, NY Department of Medicine, Albert Einstein College of Medicine, Bronx, NY.
authors: Xueliang
authors: X
authors: Du
authors: Department of Pharmaceutical and Biomedical Sciences, University of Salerno, Salerno, Italy.
authors: Anna
authors: A
authors: Carratú
authors: Department of Physiology and Biophysics, Albert Einstein College of Medicine, Bronx, NY.
authors: Gary J
authors: GJ
authors: Gerfen
authors: Institute of Pediatrics, Department of Medical and Surgical Sciences, University of Foggia, Foggia, Italy.
authors: Maria
authors: M
authors: D'Apolito
authors: Department of Clinical and Experimental Medicine, University of Foggia, Foggia, Italy.
authors: Ida
authors: I
authors: Giardino
authors: Department of Biomedical Science, University of Padua, Padua, Italy.
authors: Andrea
authors: A
authors: Rasola
authors: Department of Biomedical Science, University of Padua, Padua, Italy.
authors: Oriano
authors: O
authors: Marin
authors: Department of Pharmacology, University of California, San Diego, La Jolla, CA.
authors: Ajit S
authors: AS
authors: Divakaruni
authors: Department of Pharmacology, University of California, San Diego, La Jolla, CA.
authors: Anne N
authors: AN
authors: Murphy
authors: Diabetes Research Center, Albert Einstein College of Medicine, Bronx, NY Department of Medicine, Albert Einstein College of Medicine, Bronx, NY.
authors: Manasi S
authors: MS
authors: Shah
authors: Diabetes Research Center, Albert Einstein College of Medicine, Bronx, NY Department of Medicine, Albert Einstein College of Medicine, Bronx, NY Department of Pathology, Albert Einstein College of Medicine, Bronx, NY michael.brownlee@einstein.yu.edu.
authors: Michael
authors: M
authors: Brownlee
mesh_terms: D002460:Cell Line; D048909:Diabetes Complications / Q000378:metabolism*; D042783:Endothelial Cells / Q000378:metabolism; D025461:Feedback, Physiological; D052216:Glucagon-Like Peptide 1 / Q000031:analogs & derivatives* / Q000378:metabolism; D005947:Glucose / Q000378:metabolism*; D006442:Glycated Hemoglobin / Q000378:metabolism; D006801:Humans; D006943:Hyperglycemia / Q000378:metabolism*; D007501:Iron / Q000378:metabolism; D053078:Membrane Potential, Mitochondrial; D008928:Mitochondria / Q000378:metabolism*; D010455:Peptides / Q000378:metabolism*; D017382:Reactive Oxygen Species / Q000378:metabolism*
chemical_list: D052216:Glucagon-Like Peptide 1; D005947:Glucose; D006442:Glycated Hemoglobin; D007501:Iron; D010455:Peptides; D017382:Reactive Oxygen Species; C114437:glucagon-like peptide-1 (9-36)-amide; C517652:hemoglobin A1c protein, human