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. 2025 Jul 17;25(1):182.
doi: 10.1186/s12902-025-01999-w.

Incretin-based approaches for type 2 diabetes therapy: effects on circulating cytokines and adipocyte's secretome

Margarita Agareva  1   2 , Svetlana Michurina  1 , Alina Tomilova  3 , Ekaterina Shestakova  3 , Anastasia Voznesenskaya  3 , Maria Sineokaya  3 , Ekaterina Zubkova  1 , Elizaveta Ratner  1 , Iurii Stafeev  4 , Yelena Parfyonova  1   2 , Marina Shestakova  2   3
Affiliations

Incretin-based approaches for type 2 diabetes therapy: effects on circulating cytokines and adipocyte's secretome

Margarita Agareva et al. BMC Endocr Disord. .

Abstract

Background: Adipose tissue secretome plays a crucial role in the mechanisms of metabolic diseases. Weight loss has a favourable effect on the adipose tissue secretome and prevents the development of type 2 diabetes mellitus (T2DM) and its complications. The most effective methods of glycaemic control are bariatric surgery (BS) and pharmacotherapy. The aim of our study is to evaluate changes in adipose tissue secretome after BS and semaglutide injections.

Methods: 17 patients with T2DM were examined before and 6 months after BS or semaglutide therapy. The examination protocol included anthropometry, clinical biochemistry, insulin resistance evaluation and collection of subcutaneous adipose tissue biopsies. Adipose derived stem cells (ADSC) were isolated from biopsies according to a standard enzymatic protocol and differentiated into white and beige adipocytes. Adipogenesis and thermogenesis were assessed by confocal microscopy. Secretome of adipocytes and cytokines plasma levels were analyzed using a MILLIPLEX panel.

Results: Following BS and semaglutide therapy, a decline in BMI, total fat content, HbA1c, and fasting blood glucose was observed. Insulin sensitivity increased only 6 months after BS. Semaglutide therapy resulted in the elevation of angiogenic and proinflammatory cytokines in adipocyte secretory profile. After BS we also detected the increase in proinflammatory cytokines both in adipocyte secretome and in plasma levels. However, the adipocyte secretome subsequent to bariatric surgery (BS) exhibited a reduced proinflammatory response in comparison to that observed following semaglutide therapy.

Conclusions: The effect of semaglutide injections directly on adipose tissue can change the function of ADSC, making them more angiogenic and adipogenic. A decrease in BMI, HbA1c and insulin resistance is achieved to a significant extent only after BS. BS-induced T2DM remission is related to lower pro-inflammatory secretion from adipocytes as compared to semaglutide. The regulation of inflammation in adipocytes may serve as a potential mechanism underlying BS-induced T2DM remission.

Keywords: Adipocytes; Adipose-derived stem cells; Cytokines; Plasma; Secretome; Type 2 diabetes.

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Conflict of interest statement

Declarations. Ethics approval and consent to participate: The study protocol is in compliance with Declaration of Helsinki and was approved by the local ethics committee of the Endocrinology Research Centre (Moscow, Russia) in the framework of prolonged project “Dynamics of hormonal-metabolic factors, markers of “metabolic memory” and phenotypic characteristics of mature and progenitor cells of adipose tissue against the background of postbariatric remission of type 2 diabetes mellitus” (protocol #13 from 13 July 2022). Written informed consent was obtained from each of the volunteers. Consent for publication: Not applicable. Competing interests: The authors declare no competing interests. Disclosure summary: Authors have nothing to disclose.

Figures

Fig. 1
Fig. 1
Changes in plasma cytokines after 6 months from semaglutide therapy and bariatric surgery. A - heatmap of cytokines concentration changes after semaglutide therapy; B - heatmap of cytokines concentration changes after bariatric surgery. Secretion data were normalized on respective cytokine concentration at start point (for medians). All changes in comparative analysis by Wilcoxon matched-pairs signed rank test have p < 0.1
Fig. 2
Fig. 2
Characterization of isolated ADSC. A - representative histogram for flow cytometry analysis of CD73 expression; B - representative histogram for flow cytometry analysis of CD105 expression; C - representative histogram for flow cytometry analysis of CD140b expression; D - quantitative analysis of thermogenesis activity in mature ADSC-derived adipocytes; E - representative images of lipid droplets and thermogenesis activity for white adipocytes; F - representative images of lipid droplets and thermogenesis activity for beige adipocytes. The data are presented as median ± SEM; Mann-Whitney rank sum U-test was used to calculate significance of differences; significance level was set at p < 0.05. Scalebar = 500 μm
Fig. 3
Fig. 3
Changes in white and beige adipocytes secretome after 6 months from semaglutide therapy. A - heatmap of cytokines concentration changes in white adipocytes secretome; B - heatmap of cytokines concentration changes in beige adipocytes secretome. Secretion data were normalized on respective cytokine concentration at start point (for medians). All changes in comparative analysis by Wilcoxon matched-pairs signed rank test have p < 0.1
Fig. 4
Fig. 4
Changes in white and beige adipocytes secretome after 6 months from bariatric surgery. A - heatmap of cytokines concentration changes in white adipocytes secretome; B - heatmap of cytokines concentration changes in beige adipocytes secretome. Secretion data were normalized on respective cytokine concentration at start point (for medians). All changes in comparative analysis by Wilcoxon matched-pairs signed rank test have p < 0.1
Fig. 5
Fig. 5
Comparison of changes in adipocyte’s secretome after 6 months from semaglutide therapy and bariatric surgery. A - heatmap of cytokines concentration changes in white adipocyte’s secretome; B - heatmap of cytokines concentration changes in beige adipocyte’s secretome. Secretion data were normalized on respective cytokine concentration in the semaglutide therapy group (for medians). All changes in comparative analysis by Wilcoxon matched-pairs signed rank test have p < 0.1
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