Increased Neuronal Depolarization Evoked by Autoantibodies in Diabetic Obstructive Sleep Apnea: Role for Inflammatory Protease(s) in Generation of Neurotoxic Immunoglobulin Fragment
Journal Title: Journal of Endocrinology and Diabetes - Year 2017, Vol 4, Issue 1
Abstract
Aim Obstructive sleep apnea increases in diabetes and morbid obesity. We tested a hypothesis that circulating autoantibodies in adult type 2 diabetes which increase in association with morbid obesity are capable of causing long-lasting neuronal depolarization and altered calcium release in mouse atrial cardiomyocytes. Methods: Protein-A eluates from plasma of 14 diabetic obstructive sleep apnea patients and 17 age-matched diabetic patients without sleep apnea were tested for effects on depolarization and neurite out growth in N2a mouse neuroblastoma cells. The mechanism of autoantibodymediated neurite outgrowth inhibition was investigated in co-incubation experiments of diabetic obstructive sleep apnea autoantibodies with specific antagonists of G-protein coupled receptors or the RhoA/ Rho kinase signaling pathway. Following long-term storage of the protein-A eluates (to allow spontaneous proteolysis and IgG subunit dissociation), plasma autoantibodies from diabetic obstructive sleep apnea, cancer or control patients were compared for enhancement of inhibitory effects on endothelial cell survival. Size exclusion chromatography performed (in the presence or absence of a specific membrane type 1- matrix metalloproteinase inhibitor) was used to characterize the IgG autoantibody subunit(s) or fragments associated with peak neurotoxicity in diabetic obstructive sleep apnea. Results: Diabetic obstructive sleep apnea (n = 14) autoantibodies caused a significant increase (P = 0.01) in membrane depolarization in N2a mouse neuroblastoma cells compared to control diabetic patients (n = 15) not suffering with obstructive sleep apnea. Process extension in N2A mouse neuroblastoma cells was significantly inhibited (P = 0.01) by diabetic obstructive sleep apnea (n = 9) autoantibodies compared to effects from identical 10 mg/ mL concentrations of control diabetic autoantibodies in patients without obstructive sleep apnea. Ten micromolar concentrations of SCH-202676, a G-protein coupled receptor antagonist (n = 5) or ten micromolar concentration of Y27632, a selective Rho kinase inhibitor (n = 6), each significantly prevented (P < 0.001) neurite outgrowth inhibition by diabetic obstructive sleep apnea autoantibodies. Autoantibodies in representative patients with obstructive sleep apnea and either atrial fibrillation or left ventricular hypertrophy evoked acute large increases in intracellular Ca2+ in HL-1 mouse atrial cardiomyocytes. The magnitude of intracellular Ca2+ release was dose-dependently significantly correlated to the electrocardiographic Cornell voltage-duration product. Gel filtration of diabetic obstructive sleep apnea autoantibodies revealed peak neurotoxicity associated with MWs corresponding to IgG light chain dimer(s), monomers or half-light chains as well as a novel 5.5 kD putative light chain fragment. Conclusions These results suggest that diabetic obstructive sleep apnea autoantibodies may induce strong depolarization in neuronal cells and alter Ca2+ signaling in atrial cardiomyocytes consistent with a role in pathophysiology in subsets of diabetic obstructive sleep apnea having comorbid atrial fibrillation or another clinically significant cardiac rhythm disturbance.
Authors and Affiliations
Mark B. Zimering, Zui Pan
Keywords
Related Articles
- EP ID EP333718
- DOI 10.15226/2374-6890/4/1/00168
- Views 78
- Downloads 0
Polycystic Ovary Syndrome: Explaining the Gynecological Aspects and Treatment Options to Patients
Polycystic Ovary Syndrome (PCOS) is one of the most prevalent conditions leading to reproductive and metabolic health concerns for women. The apparently disparate consequences of this disorder ranging from menstrual dysf...
Surgery in Refractory Amiodarone-Induced Thyrotoxicosis
Background: Thyroidectomy is a challenging treatment for refractory amiodarone induced thyrotoxicosis (AIT). Objectives: The authors’ aim in this article is to conduct a systematic review of the currently available lite...
Confronting Complacency in the Face of Calamity: Mobilizing for the Home Front War against Diabetes
Despite the damage Type 2 Diabetes (DM2) is wreaking on vulnerable families and communities, the US clinical, public health and scientific communities have not yet mobilized for a public health war against DM2. This war...
Strategies of Hyperglycemia Management among Patients with Diabetic Nephropathy, Renal Impairment, Hypertension and Lipid Disorders
Diabetic nephropathy, a microvascular complication, usually starts by the development of incipient nephropathy (microalbuminuria), then proteinuria, reduced glomerular filtration rate and finally renal impairment or Chro...
Euro-Collins Solution for a Lower-Cost Preservation of Donor’s Pancreas
This paper aims to evaluate results from pancreas-kidney transplants, in type 1 diabetes mellitus patients, comparing the use of Euro-Collins and Belzer or Celsior solutions for organ storage while awaiting transplant. O...