Neurotransmitter Alterations in Prediabetes and Type 2 Diabetes Mellitus: A Narrative Review.

Prediabetes and early type 2 diabetes mellitus (T2D) are increasingly recognized as states of both metabolic and neurochemical dysregulation. This narrative review synthesizes emerging evidence of alterations in key neurotransmitter systems-dopamine, serotonin, norepinephrine, gamma-aminobutyric acid, and glutamate-in individuals with prediabetes and diabetes. Beyond peripheral insulin resistance and β-cell dysfunction, disturbances in the central nervous system, especially related to neurotransmitter signaling, may play a role in disease onset and progression. Neuroimaging studies reveal early imbalances in excitatory and inhibitory neurotransmitters, while biochemical and histological findings demonstrate altered receptor expression in both the brain and pancreatic islets. These changes affect metabolic control and are implicated in mood, cognition, and feeding behavior. We investigate the mechanistic links between neurotransmitter dysfunction and glucose metabolism, including the roles of brain insulin resistance, inflammation, mitochondrial stress, and gut-brain axis signaling. Finally, we discuss therapeutic strategies that target neurochemical pathways and highlight the need for longitudinal, sex-aware, and multi-omics studies to refine early interventions. Understanding the neurobiological roots of early T2D could revolutionize risk assessment and open doors for new neuro-metabolic treatments.