# Metformin Induces Changes in Sphingosine-1-Phosphate-Related Signaling in Diabetic Mice Brain

## TL;DR

This study shows that metformin, a diabetes drug, can reverse harmful brain changes in diabetic mice by affecting sphingosine-1-phosphate signaling and reducing inflammation.

## Contribution

The study reveals metformin's impact on sphingosine-1-phosphate signaling and inflammation in the brain of diabetic mice, offering new insights into its neuroprotective effects.

## Key findings

- Metformin reversed elevated SPHK2 and S1PR3 mRNA levels in diabetic mice hippocampus.
- Metformin reduced pro-inflammatory cytokines IL-6 and TNF-α and upregulated S1PR1.
- Metformin partially restored hippocampal ultrastructural changes like mitochondrial swelling and capillary thickening.

## Abstract

Type 2 diabetes mellitus (T2DM) is a chronic disease that has become a serious health problem worldwide. Moreover, increased systemic and cerebrovascular inflammation is one of the major pathophysiological features of T2DM, and a growing body of evidence emphasizes T2DM with memory and executive function decline. Bioactive sphingolipids regulate a cell’s survival, inflammatory response, as well as glucose and insulin signaling/metabolism. Moreover, current research on the role of sphingosine kinases (SPHKs) and sphingosine-1-phosphate receptors (S1PRs) in T2DM is not fully understood, and the results obtained often differ. The aim of the present study was to evaluate the effect of metformin (anti-diabetic agent, MET) on the brain’s sphingosine-1-phosphate-related signaling and ultrastructure in diabetic mice. Our results revealed elevated mRNA levels of genes encoding sphingosine kinase 2 (SPHK2) and sphingosine-1-phosphate receptor 3 (S1PR3), which was accompanied by downregulation of sphingosine-1-phosphate receptor 1 (S1PR1) in the hippocampus of diabetic mice. Simultaneously, upregulation of genes encoding pro-inflammatory cytokines interleukin 6 (IL-6) and tumor necrosis factor α (TNF-α) was observed. Administration of MET significantly reversed changes in mRNA levels in the hippocampus and reduced Sphk2, Il6, and Tnf, with concomitant upregulation of S1pr1 gene expression. Ultrastructural analysis of diabetic mice hippocampus revealed morphological alterations in neurons, neuropil, and capillaries that were manifested as mitochondria swelling, blurred synaptic structure, and thickened basal membrane of capillaries. The use of MET partially reversed those changes. Our research emphasizes the important role of insulin sensitivity modulation by metformin in the regulation of SPHKs and S1PRs and inflammatory gene expression in a murine model of T2DM.