title: Autophagy in the brains of young patients with poorly controlled T1DM and fatal diabetic ketoacidosis.
abstract: Semi-quantitative neuroradiologic studies, quantitative neuron density studies and immunocytochemistry markers of oxidative stress and neuroinflammation indicate neuronal injury and deficits in young patients with chronic poorly controlled type 1 diabetes mellitus (T1DM). Present data suggest that pathogenesis of the neuronal deficits in young patients, who die as the result of diabetic ketoacidosis (DKA) and brain edema (BE), does not involve apoptosis, a prominent form of regulated cell death in many disease states. To further address this we studied mediators of macroautophagy, endoplasmic reticulum (ER) stress and apoptosis. In all areas studied we demonstrated increased levels of macroautophagy-associated proteins including light chain-3 (LC3) and autophagy related protein-4 (Atg4), as well as increased levels of the ER-associated glucose-regulated protein78/binding immunoglobulin protein (GRP78/BiP) in T1DM. In contrast, cleaved caspase-3 was rarely detected in any T1DM brain regions. These results suggest that chronic metabolic instability and oxidative stress may cause alterations in the autophagy-lysosomal pathway but not apoptosis, and macroautophagy-associated molecules may serve as useful candidates for further study in the pathogenesis of early neuronal deficits in T1DM.
authors.affiliation: Department of Pediatrics, Section of Pediatric Endocrinology, Georgia Health Sciences University, Augusta, GA, USA. whoffman@georgiahealth.edu
authors.forename: William H
authors.initials: WH
authors.lastname: Hoffman
authors.forename: John J
authors.initials: JJ
authors.lastname: Shacka
authors.forename: Anuska V
authors.initials: AV
authors.lastname: Andjelkovic
mesh_terms: D000293:Adolescent; D017209:Apoptosis; D001343:Autophagy; D000071183:Autophagy-Related Proteins; D001929:Brain Edema / Q000209:etiology / Q000378:metabolism / Q000473:pathology*; D003546:Cysteine Endopeptidases / Q000235:genetics / Q000378:metabolism; D003922:Diabetes Mellitus, Type 1 / Q000150:complications / Q000378:metabolism / Q000473:pathology*; D016883:Diabetic Ketoacidosis / Q000209:etiology / Q000378:metabolism / Q000473:pathology*; D000091342:Endoplasmic Reticulum Chaperone BiP; D059865:Endoplasmic Reticulum Stress / Q000502:physiology; D017809:Fatal Outcome; D005260:Female; D006360:Heat-Shock Proteins / Q000378:metabolism; D006801:Humans; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D009474:Neurons / Q000378:metabolism; D018384:Oxidative Stress
chemical_list: D000071183:Autophagy-Related Proteins; D000091342:Endoplasmic Reticulum Chaperone BiP; C000717247:HSPA5 protein, human; D006360:Heat-Shock Proteins; C477012:MAP1LC3A protein, human; D008869:Microtubule-Associated Proteins; C474025:ATG4A protein, human; D003546:Cysteine Endopeptidases
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