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.

Ketosis may promote brain macroautophagy by activating Sirt1 and hypoxia-inducible factor-1

“…This speculation is consistent with a recent report demonstrating a 3-4-fold increase autophagosomes in the brain neurons of mice fasted for 48 h [88,89]. Moreover, macroautophagy is markedly up-regulated in the brains of type 1 diabetics who have died of ketoacidosis [90].…”

Hyperketonemia (Acetoacetate) Upregulates NADPH Oxidase 4 and Elevates Oxidative Stress, ICAM-1, and Monocyte Adhesivity in Endothelial Cells

“…Previous studies have demonstrated that the ketones, especially AA, can generate superoxide radicals and induce cytokine and adhesion molecule expression, and that ketonemic diabetics have high levels of oxidative stress compared to those of normoketonemic diabetic patients [13,14,16,20,24,36,37,38,39,40,41,42,43,44,45,46,47,48,49,50,51,52,53,54]. We observed that AA was significantly able to upregulate NOX4 expression and NADPH oxidase activity, while BHB failed to produce any adverse effects in HUVEC.…”

Cellular metabolic and autophagic pathways: Traffic control by redox signaling

“…The autophagy pathway is sensitive to alterations in glucose metabolism (Figure 3). In the brain, young patients with poorly controlled Type I diabetes exhibit increased autophagy protein LC3 and Atg4, increased ER-associated glucose-regulated protein78/binding immunoglobulin protein (GRP78/BiP) [70]. In stroke and cerebral ischemia, oxygen and glucose deprivation occurs.…”