Toxic Immunoglobulin Light Chain Auto antibodies are Associated with a Cluster of Severe Complications in Older Adult Type 2 Diabetes
Journal Title: Journal of Endocrinology and Diabetes - Year 2016, Vol 3, Issue 1
Abstract
Aims: To assess neuronal depolarization evoked by autoantibodies in diabetic depression compared to depolarization evoked by autoantibodies in control patients. To determine whether a subset of severe (late-onset) diabetic complications may be mediated in part by toxic immunoglobulin light chains that may increase in diabetic nephropathy. Methods: Protein-A eluates from plasma of 21 diabetic depression patients and 37 age-matched controls were tested for depolarization in hippocampal or immature neurons. Subsets of depolarizing or non-depolarizing autoantibodies were tested for neurite outgrowth inhibition in N2A neuroblastoma cells or the ability to modulate Ca2+ release in HL-1 atrial cardiomyocytes or in endothelial cells. The stability of depolarizing autoantibodies was investigated by heat treatment (56°C x 30 minutes) or following prolonged exposure to the pro-protein convertase, furin. Gel filtration of active depolarizing autoantibodies was performed to determine the apparent molecular mass of peak neurotoxicity associated with the autoantibodies. Results: Diabetic depression (n = 21) autoantibodies caused significantly greater mean depolarization in neuroblastoma cells (P < 0.01) compared to autoantibodies in diabetic (n = 15) or non-diabetic (n = 11) patients without depression. Depolarizing autoantibodies caused significantly more (P=0.011) inhibition of neurite outgrowth in neuroblastoma cells than non-depolarizing autoantibodies (n = 10) and they evoked sustained, global intracellular Ca2+ release in atrial cardiomyocytes or in endothelial cells. A subset of older diabetic patients suffering with a cluster of nephropathy, non-ischemic cardiomyopathy and/or depression demonstrated the presence of stable light chain dimers having apparent MW of 46 kD and associated with peak neurotoxicity in neuroblastoma cells. Conclusion: These data suggest that autoantibodies in older adult diabetic depression cause long-lasting depolarization in hippocampal neurons including adult dentate gyrus neural progenitor cells. The autoantibodies may impair adult dentate gyrus neurogenesis associated with treatment-refractory depression via several mechanisms including suppression of neurite outgrowth, and alteration of membrane excitability. Stable, toxic light chain autoantibody components may contribute to a cluster of severe (late-onset) complications characterized by dysfunction in highly vascularized tissues.
Authors and Affiliations
Mark B Zimering, Mirkovic N, Pandya M, Zimering JH, Behnke JA, Thakker Varia S, Alder J, Donnelly RJ
Keywords
Related Articles
- EP ID EP333378
- DOI 10.15226/2374-6890/3/1/00141
- Views 99
- Downloads 0
Pentraxin 3 as A Cardiovascular Marker in Primary Hyperparathyroidism
Aim: Pentraxin 3 (PTX3) is an acute-phase glycoprotein, which is increased in patients with cardiovascular disease (CVD) and considered as a predictor of CVD in the general population. Accumulating evidence suggests that...
Extra-Skeletal and Endocrine Functions and Toxicity of Vitamin D
During the past 15 years, the knowledge related to vitamin D has markedly expanded, especially with reference to the hormonal and extra-skeletal effects of vitamin D. The understanding of the biological and physiological...
Beneficial Effects of a 1-Year Lifestyle Intervention on Metabolic Abnormalities in Overweight and Obese Schoolchildren in Sousse Tunisia: A Pre-Post Quasi- Experimental Study with Control Group
Introduction: The prevalence of obesity in children has increased worldwide during the most recent decades. In this context, we have conducted this study in the purpose to investigate changes in metabolic syndrome in ove...
Diabetic Peripheral Neuropathy: Current Concepts and Future Perspectives
Background: Peripheral Diabetic Neuropathy (PDN) is the clinical condition and one of the most common complications of diabetes affecting approximately 50% of people. Out of it, 16% to 33% of the patients manifest Neurop...
Fitness Level is Associated with Sex-Specific Regional Fat Differences in Normal Weight Young Adults
Objectives: To characterize regional body composition and insulin sensitivity differences between young adults who were normal weight with either high or low fitness determined by VO2 peak. We hypothesized that higher fi...