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Sitagliptin phosphate ameliorates chronic inflammation in diabetes mellitus via modulating macrophage polarization

ABSTRACT: Aim: To investigate the effect and mechanism of Sitagliptin phosphate on inflammation and macrophage polarization in a mouse model of type 2 diabetes. Methods: In vitro, Raw264.7 cells were cultured with a high concentration of glucose (HG) and sitagliptin phosphate (SIG). The levels of inflammatory factors and the regulation of macrophage polarization were investigated, and the differentially expressed genes between HG and HG+SIG intervention were analyzed and enriched through transcriptomics. In vivo, C57BL/6J male mice were treated with HFD+STZ to establish a type 2 diabetes mouse model were investigated the effects of regulation of macrophage polarization in the pancreas and visceral adipose tissue. Results:In vitro cell experiments and transcriptomics showed that Sitagliptin phosphate decreased the secretion of inflammatory factors IL-6 and TNF-α induced by high-glucose, and increased secretion of anti-inflammatory factor IL-10 by enhancing macrophage polarization. In vivo, the body weight and abdominal visceral fat weight, the ratio of visceral fat weight to body weight and fasting blood glucose were significantly increased in the DM group compared with the Control (P<0.05), Sitagliptin phosphate treatments reversed the changes in the DM group. Moreover, histological analysis showed that compared with the Control group, the size of visceral adipocytes, hepatocyte lipid deposition and the ratio of M1/M2 macrophage were higher in the DM group, which were reversed by Sitagliptin phosphate treatments (P<0.05), insulin treatments did not have a significant effect(P＞0.05).Mechanistically, Western blot showed that compared with the normal group, HG upregulated the expression of mTORc1 protein, P-65 phosphorylation and P-65 protein expression in Raw264.7 cells (P<0.05), downregulated the expression of IKKβ (P<0.05) and PPAR-γ proteins (P<0.05), Sitagliptin phosphate and insulin treatments rescued these changes. Conclusion: These results indicated that Sitagliptin phosphate reduced high glucose-induced inflammation by improving the imbalance of macrophage polarization via modulating the mTORc1/ PPAR-γ/NF-κB in vitro and in vivo.

ORGANISM(S): Mus musculus

PROVIDER: GSE293313 | GEO | 2025/04/03

REPOSITORIES: GEO

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Project description:The aim of the study was to explore the effect of topically administered sitagliptin, an inhibitor of the enzyme dipeptidyl peptidase-4, on the retinal expression patterns of an experimental model of DR. Background: Synaptic dysfunction and neuronal damage have been extensively associated with diabetic retinopathy (DR). Our group evidenced that chronic hyperglycemia reduces the retinal expression of presynaptic proteins, which are crucial for a proper synaptic function. The aim of the study was to explore the effect of topically administered sitagliptin, an inhibitor of the en-zyme dipeptidyl peptidase-4, on the retinal expression patterns of an experimental model of DR. Methods: Transcriptome analysis was performed comparing the retinas of 10 diabetic (db/db) mice randomly treated with sitagliptin eye drops (10 mg/mL) twice daily, and the reti-nas of 10 additional db/db mice that received vehicle eye drops. 10 non diabetic mice (db/+) were used as control group. Gene Ontology (GO) and Reactome databases were used to assess the Gene Set Enrichment Analysis (GSEA) in order to explore the most enriched biological pathways among groups. The most differentiated genes of these pathways were validated through quantitative RT-PCR. Results: Transcriptome analysis revealed that sitagliptin eye drops have a significant effect on retinal expression patterns and that neurotransmission was the most enriched biological process. Our study evidenced enriched pathways that contain genes involved in membrane trafficking, transmission across chemical synapses, vesi-cle-mediated transport, neurotransmitter receptors and postsynaptic signal transmission with negative regulation of signaling as a consequence of neuroprotector treatment with sitagliptin. This improves the modulation of macromolecule biosynthetic process with positive regulation of cell communication which provides beneficial effects for neuronal metabolism. Conclu-sions: This study suggests that topical administration of sitagliptin ameliorates the abnormali-ties on presynaptic and postsynaptic signal transmission during experimental DR, and that this improvement is one of the main mechanisms behind the previously demonstrated beneficial effects.

Project description:Background: Macrophage polarization programs, commonly referred to as âclassicalâ and âalternativeâ activation, are widely considered as distinct states that are exclusive of one another, and are associated with different functions such as inflammation and wound healing, respectively. In a number of disease contexts, such as traumatic brain injury (TBI), macrophage polarization influences the extent of pathogenesis, and efforts are underway to eliminate pathogenic subsets. However, previous studies have not distinguished whether the simultaneous presence of both classical and alternative activation signatures represents the admixture of differentially polarized macrophages, or if they have adopted a unique state characterized by components of both classical and alternative activation. Results: We analyzed the polarization of individual macrophages responding to TBI using single-cell RNA sequencing. Analysis of signature polarization genes revealed diverse activation states, including M(IL4), M(IL10), and M(LPS, IFNÎ³). However, the expression of a given polarization marker was no more likely than at random to predict simultaneous expression or repression of markers of another polarization program within the same cell, suggesting a lack of exclusivity in macrophage polarization states in vivo in TBI. Also unexpectedly, individual TBI macrophages simultaneously expressed high levels of signature polarization genes across two or three different polarization states, and in several distinct and seemingly incompatible combinations. Conclusions: Single-cell gene expression profiling demonstrated that monocytic macrophages in TBI are not comprised of distinctly polarized subsets, but are uniquely and broadly activated. TBI macrophage activation in vivo is deeply complex, with individual cells concurrently adopting both inflammatory and reparative features. These data provide physiologically relevant evidence that the early macrophage response to TBI is comprised of novel activation states that are discordant with the current paradigm of macrophage polarizationâa key consideration for therapeutic modulation. Monocyte derived macrophages were isolated from the ipsilateral hemisphere of mouse brains one day following traumatic brain injury elicited by control cortical impact in C57BL/6 adult male mice. Single-cells were isolated and processed for RNA sequencing using a Fluidigm C1 integrated fluidic circuit chip. 45 biological replicates were analyzed.

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Sitagliptin phosphate ameliorates chronic inflammation in diabetes mellitus via modulating macrophage polarization

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