Central Responses to SGLT2 Inhibition: Distinguishing Direct CNS Pharmacology from the Brain–Kidney–Metabolism Axis
- 1Research Institute for Convergence of Biomedical Science and Technology, Pusan National University Yangsan Hospital, Yangsan 50612, Republic of Korea
- 2Division of Endocrinology and Metabolism, Department of Internal Medicine, Pusan National University Yangsan Hospital, Pusan National University School of Medicine, Yangsan 50612, Republic of Korea
Abstract
Sodium-glucose cotransporter 2 (SGLT2) inhibitors improve cardiovascular and kidney outcomes through mechanisms that extend beyond glycemic control. Emerging studies report changes in hypothalamic and brainstem physiology following SGLT2 inhibitor administration, but the evidentiary meaning of these observations remains uncertain. This review critically evaluates clinical, in vivo, ex vivo, and cellular evidence linking SGLT2 inhibition to central metabolic regulation. We distinguish three claims that are often conflated: central pharmacological capacity after direct neural exposure, central nervous system (CNS) adaptation after systemic treatment, and therapeutically relevant CNS target engagement with causal mediation. Candidate pathways include hypothalamic nutrient sensing, insulin responsiveness, melanocortin signaling, ketone availability, glial inflammation, redox regulation, and autonomic activity. We propose a bidirectional brain–kidney–metabolism framework in which renal glucose and sodium loss generate metabolic, hormonal, inflammatory, hemodynamic, and potentially neural signals that are integrated by hypothalamic and brainstem circuits. These circuits may then convey autonomic and neuroendocrine outputs to peripheral organs. Current evidence supports central responsiveness and CNS adaptation to systemic treatment, but not a unified direct SGLT2-dependent brain mechanism. Compound-specific unbound CNS pharmacokinetics, orthogonal cell-specific target validation, compartment-restricted models, selective renal-afferent manipulation, and longitudinal human phenotyping are required to establish causality. The proposed framework complements, rather than replaces, established renal and tissue-specific mechanisms.
Related
- Distinguishing hyperparathyroidism from insulin-like growth factor I–driven calcium–phosphate metabolism changes in acromegaly
- Extracellular Vesicles and Choline Metabolism in Neonatal Bronchopulmonary Dysplasia: A Systems-Pharmacology Framework for Regenerative Therapy
- P2Y12 inhibition, adenosine signaling, and bone remodeling: differential skeletal pharmacology of antiplatelet agents
- Ensemble signal detection reveals target-specific temporal risk of hypokalemia after immune checkpoint inhibition: a translational pharmacology framework
- NRF2 signalling in environmental metal and metalloid neurotoxicity: distinguishing stress responses from functional neuroprotection
BibTeX
@article{kim2026central,
title = {{Central Responses to SGLT2 Inhibition: Distinguishing Direct CNS Pharmacology from the Brain–Kidney–Metabolism Axis}},
author = {Dong Hee Kim and Min Jin Lee and Seung Hee Lee and Joo Yeon Kim and Ji Hyun Bae and Ah Reum Khang and Yang Ho Kang and Dongwon Yi},
journal = {International Journal of Molecular Sciences},
year = {2026},
month = oct,
doi = {10.3390/ijms27219514},
url = {https://www.mdpi.com/1422-0067/27/21/9514},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Central Responses to SGLT2 Inhibition: Distinguishing Direct CNS Pharmacology from the Brain–Kidney–Metabolism Axis
AU - Dong Hee Kim
AU - Min Jin Lee
AU - Seung Hee Lee
AU - Joo Yeon Kim
AU - Ji Hyun Bae
AU - Ah Reum Khang
AU - Yang Ho Kang
AU - Dongwon Yi
PY - 2026
DA - 2026/10/24
JO - International Journal of Molecular Sciences
DO - 10.3390/ijms27219514
UR - https://www.mdpi.com/1422-0067/27/21/9514
AB - Sodium-glucose cotransporter 2 (SGLT2) inhibitors improve cardiovascular and kidney outcomes through mechanisms that extend beyond glycemic control. Emerging studies report changes in hypothalamic and brainstem physiology following SGLT2 inhibitor administration, but the evidentiary meaning of these observations remains uncertain. This review critically evaluates clinical, in vivo, ex vivo, and cellular evidence linking SGLT2 inhibition to central metabolic regulation. We distinguish three claims that are often conflated: central pharmacological capacity after direct neural exposure, central nervous system (CNS) adaptation after systemic treatment, and therapeutically relevant CNS target engagement with causal mediation. Candidate pathways include hypothalamic nutrient sensing, insulin responsiveness, melanocortin signaling, ketone availability, glial inflammation, redox regulation, and autonomic activity. We propose a bidirectional brain–kidney–metabolism framework in which renal glucose and sodium loss generate metabolic, hormonal, inflammatory, hemodynamic, and potentially neural signals that are integrated by hypothalamic and brainstem circuits. These circuits may then convey autonomic and neuroendocrine outputs to peripheral organs. Current evidence supports central responsiveness and CNS adaptation to systemic treatment, but not a unified direct SGLT2-dependent brain mechanism. Compound-specific unbound CNS pharmacokinetics, orthogonal cell-specific target validation, compartment-restricted models, selective renal-afferent manipulation, and longitudinal human phenotyping are required to establish causality. The proposed framework complements, rather than replaces, established renal and tissue-specific mechanisms.
SN - 1422-0067
ER -