A groundbreaking study recently published in the “Cerebral Cortex” journal has illuminated the prospects of a novel treatment approach for cognitive decline induced by diabetes mellitus (DM). The international team, led by Dr. Zhang Xi and colleagues from the Wenzhou Medical University in China, has unveiled the neuroprotective effects of Fibroblast growth factor 21 (FGF21) in combating the adverse cognitive consequences associated with DM. This research marks a significant stride forward in understanding the intricate connection between metabolic disorders and cognitive function, and it could potentially lead to new therapeutic strategies for individuals suffering from diabetes-induced cognitive decline (DICD).

Diabetes Mellitus and Its Cognitive Toll

Diabetes mellitus, a global health challenge affecting millions, poses a risk not only to physical health but also to cognitive abilities. Prolonged high blood sugar levels are known to cause damage to vessels and nerves, amongst which include those critical to the central nervous system. This often precipitates a range of cognitive deficits, commonly referred to as diabetes-induced cognitive decline (DICD), encompassing issues with memory, learning, and executive function.

Introduction of FGF21 as a Therapeutic Agent

The novelty of Dr. Zhang Xi and the team’s research lies in the application of Fibroblast growth factor 21 (FGF21). FGF21 is a hormone secreted primarily by the liver, known to play a critical role in glucose and lipid metabolism. Until now, its therapeutic potential for neurodegenerative diseases remained largely unexplored in practical settings. This study investigates the therapeutic effects of FGF21 when administered directly to the brain through an intracerebroventricular (i.c.v.) infusion, targeting the mitigation of DICD.

Methodology: A Metabolic and Neurological Perspective

The team employed advanced 1H nuclear magnetic resonance (NMR)-based metabolomics in conjunction with 13C NMR spectroscopy, alongside intravenous [1-13C]-glucose infusion, to explore the underlying metabolic mechanisms of FGF21’s effects. These sophisticated techniques enabled a detailed analysis of the cerebral metabolism alterations associated with DICD and the subsequent impact of FGF21 intervention.

Promising Findings in Memory and Learning Performance

The findings of the study are promising. Mice with DICD exhibited substantial improvement in learning and memory performance following the i.c.v. FGF21 infusion. Neuronal loss and apoptosis, particularly in the hippocampus and cortex—regions of the brain essential for cognitive function—were notably mitigated. The comprehensive metabolomics results accentuated FGF21’s modulation of metabolic shifts associated with glucose and neurotransmitter metabolism, evidenced by the replenished enrichment of specific 13C-labeled metabolites derived from [1-13C]-glucose, which are vital for cognitive performance.

The Role of PI3K/AKT/GSK-3β Signaling Pathway

A striking observation was the involvement of the PI3K/AKT/GSK-3β signaling pathway, known for its significant role in cell survival and neuroprotection. The researchers proposed that FGF21 potentially rehabilitates neuron injury and metabolic dysfunctions in DICD by reactivating this crucial pathway, disturbed by diabetes.

Implications for the Future of DICD Treatment

The implications of this breakthrough are far-reaching. With the establishment of FGF21 as a potent neuroprotective agent in diabetes-related cognitive deterioration, future pharmacological strategies could evolve towards the incorporation of FGF21 mimicry or analogs in managing not only DM but also the consequent neurodegenerative sequelae.

Conclusion and the Way Forward

Dr. Zhang Xi’s work concretizes the prospect of developing definitive treatments targeted at the neuronal aspects of diabetes. The study serves as a bedrock upon which further research may expand, ultimately paving the way for clinical trials and transforming the therapeutic landscape for individuals living with DM and its cognitive ramifications.

DOI: 10.1093/cercor/bhad502

References

1. Zhang Xi, et al. (2024). Fibroblast growth factor 21 alleviates diabetes-induced cognitive decline. Cerebral Cortex. DOI: 10.1093/cercor/bhad502
2. Kharitonenkov, A., Shanafelt, A. B. (2008). FGF21: a novel prospect for the treatment of metabolic diseases. Current Opinion in Investigational Drugs, 9(5), 501-507.
3. Liang, Q., Zhong, L., Zhang, J., et al. (2014). FGF21 maintains glucose homeostasis by mediating the cross talk between liver and brain during prolonged fasting. Diabetes, 63(12), 4064-4075. DOI: 10.2337/db14-0541
4. Yau, S. Y., Li, A., Hoo, R. L. C., et al. (2014). Physical exercise-induced hippocampal neurogenesis and antidepressant effects are mediated by the adipocyte hormone adiponectin. Proceedings of the National Academy of Sciences, 111(44), 15810-15815. DOI: 10.1073/pnas.1415219111
5. Adams, A. C., Kharitonenkov, A. (2012). FGF21: The center of a transcriptional nexus in metabolic regulation. Current Diabetes Reviews, 8(4), 285-293. DOI: 10.2174/157339912802083523

Keywords

1. Diabetes-induced cognitive decline
2. FGF21 neuroprotection
3. Metabolic brain alterations
4. PI3K/AKT/GSK-3β signaling pathway
5. Diabetes treatment breakthrough