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The brain in diabetes: molecular changes in neurons and their implications for end-organ damage
Joshua P Klein1, Stephen G Waxman
1Department of Neurology and PVA/EPVA Center for Neuroscience and Regeneration Research, Yale University School of Medicine, New Haven 06510, USA.
Abstract:
Although secondary end-organ damage in diabetes has generally been thought to result from long-term passive shunting of excess glucose through alternative metabolic pathways, recent studies have elucidated a second mechanism of pathogenesis that involves active changes in gene expression in neurons of the CNS. These changes in gene expression result in molecular and functional changes that can become maladaptive over time. In this review, we examine two neuronal populations in the brain that have been studied in human beings and animal models of diabetes. First, we discuss overactivation of magnocellular neurosecretory cells within the hypothalamus and how it relates to the development of diabetic nephropathy. And second, we describe how changes in hippocampal synaptic plasticity can lead to cognitive and behavioural deficits in chronic diabetes. Changes in neuronal gene expression in diabetes represent a new pathway for diabetic pathogenesis. This pathway may hold clues for the development of therapies that, via the targeting of neurons, can slow or prevent the development of diabetic end-organ damage.
Insights
Diabetes causes end-organ damage through new pathways involving gene expression changes in the central nervous system (CNS). Targeting these neuronal changes may offer novel therapies for diabetic complications.
Area of Science:
- Neuroscience
- Endocrinology
- Diabetology
Background:
- Diabetic end-organ damage is traditionally linked to excess glucose metabolism.
- Emerging evidence reveals active alterations in CNS neuronal gene expression as a key pathogenic mechanism.
Purpose of the Study:
- To review the role of neuronal gene expression changes in diabetic pathogenesis.
- To examine specific neuronal populations affected in diabetes: hypothalamic magnocellular neurosecretory cells and hippocampal neurons.
Main Methods:
- Review of existing human and animal model studies on diabetes and neuronal function.
- Analysis of the link between hypothalamic overactivation and diabetic nephropathy.
- Examination of hippocampal synaptic plasticity alterations and their cognitive/behavioral consequences.
Main Results:
- Overactivation of hypothalamic magnocellular neurosecretory cells contributes to diabetic nephropathy.
- Altered hippocampal synaptic plasticity leads to cognitive and behavioral deficits in chronic diabetes.
- Neuronal gene expression changes represent a distinct pathway in diabetes pathogenesis.
Conclusions:
- Changes in neuronal gene expression offer a new understanding of diabetic complications.
- Targeting CNS neurons presents a potential therapeutic strategy to mitigate or prevent diabetic end-organ damage.