Lysosomal Acidification Reserve in Diabetic Encephalopathy: From Adaptive Homeostasis to Functional Failure

Abstract

Diabetic encephalopathy (DE) is a complex neurological disorder arising from chronic metabolic dysregulation and involving synaptic dysfunction, neuroinflammation, impaired proteostasis and neurodegenerative changes. The autophagy–lysosomal pathway (ALP) is a central network for maintaining intracellular homeostasis in neurons and glial cells. However, studies of lysosomal dysfunction in diabetes have largely relied on endpoint measures, including lysosomal abundance, membrane markers, lysosomal enzyme activity, autophagic flux and steady-state luminal acidity. Although these parameters can identify lysosomal dysfunction, they provide limited insight into the capacity of lysosomes to maintain or restore function when challenged by sustained metabolic stress. Here, we propose lysosomal acidification reserve capacity (LARC) as a conceptual framework for understanding lysosomal acidification as a dynamic functional property governed by proton transport, ion homeostasis, membrane integrity, organelle interactions and degradative demand. Integrating mechanistic evidence from diabetes and neurodegenerative disorders, we propose that chronic metabolic stress may initially increase or redistribute lysosomal degradative demand, while compensatory mechanisms preserve apparent homeostasis. With persistent stress, however, the capacity to sustain or recover an acidic lumen may progressively decline, increasing the fraction of lysosomes with limited recovery capacity and predisposing cells to impaired ALP-dependent quality control and downstream injury. This framework further suggests that lysosomal heterogeneity may reflect dynamic functional states rather than simply the coexistence of fixed subpopulations. A key, experimentally testable prediction is that impaired lysosomal re-acidification may emerge before overt abnormalities in steady-state luminal acidity. We discuss how metabolic sensing and transcriptional regulation, membrane and ion homeostasis, lysosomal damage repair and ALP-mediated quality control could shape this reserve, and propose experimental strategies to directly test whether LARC represents a functional link between chronic metabolic stress and neuronal homeostatic failure in DE.