Sitagliptin Reduces Inflammation and Chronic Immune Cell Activation in HIV+ Adults With Impaired Glucose Tolerance

Best, Conor; Struthers, Heidi; Laciny, Erin; Royal, Michael; Reeds, Dominic N.; Yarasheski, Kevin E.

doi:10.1210/jc.2015-1531

Cited by 34 publications

(19 citation statements)

References 37 publications

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“…Another clinical trial showed somewhat similar findings to ours [56]. In HIV-positive glucose intolerant patients, who almost universally have systemic inflammation, sitagliptin significantly decreased plasma IP-10 and sCD14 (a marker of monocyte activation) and AT monocyte chemotactic protein-1 (important in facilitating inflammation) compared to placebo.…”

Section: Plos Onesupporting

confidence: 84%

Feasibility of quantifying change in immune white cells in abdominal adipose tissue in response to an immune modulator in clinical obesity

et al. 2020

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Background Obesity is often associated with inflammation in adipose tissue (AT) with release of mediators of atherogenesis. We postulated that it would be feasible to collect sufficient abdominal AT to quantify changes in a broad array of adaptive and innate mononuclear white cells in obese non-diabetic adults in response to a dipeptidyl protease inhibitor (DPP4i), known to inhibit activation of immune white cells. Methods Adults 18-55 years-of-age were screened for abdominal obesity and insulin resistance or impaired glucose tolerance but without known inflammatory conditions. Twenty-one eligible participants consented for study and were randomized 3:1 to receive sitagliptin (DPP4i) at 100mg or matching placebo daily for 28 days. Abdominal AT collected by percutaneous biopsy and peripheral blood mononuclear cell fractions were evaluated before and after treatment; plasma was stored for batch testing. Results Highly sensitive C-reactive protein, a global marker of inflammation, was not elevated in the study population. Innate lymphoid cells (ILC) type 3 (ILC-3) in abdominal AT decreased with active treatment compared with placebo (p = 0.04). Other immune white cells in AT and

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Section: Plos Onesupporting

confidence: 84%

Feasibility of quantifying change in immune white cells in abdominal adipose tissue in response to an immune modulator in clinical obesity

et al. 2020

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“…Although these results may differ from the reported broad anti-inflammatory effects of other DPP-4 inhibitors in adipose tissue in animals [15,22,23], they appear consistent with limited data on the effect of DPP-4 inhibitors on adipose tissue inflammation in humans [19]. There was a slightly greater decline in adipose tissue abundance of MCP-1 mRNA levels after 8-week sitagliptin treatment compared with placebo in HIV-positive people with impaired glucose tolerance [19]; however, sitagliptin had no effect on the other measured marker of inflammation in that study, EMR-1 [19]. The results of the present study, which include a broad array of inflammatory markers and reflect transcriptional and translational expression of inflammatory proteins as well as inflammation pathway activation, provide more definitive support for a neutral effect of saxagliptin on adipose tissue inflammation in overweight or obese humans at increased risk of Type 2 diabetes.…”

Section: Discussionsupporting

confidence: 73%

“…In preclinical studies, DPP-4 inhibitors reduced trans-endothelial migration and inflammatory cytokine production by T cells in vitro [13,14], and reduced inflammation in both atherosclerotic plaque and adipose tissue in vivo in mice [15,16]. In humans, DPP-4 inhibitors decreased multiple blood pro-inflammatory markers in those with Type 2 diabetes [17,18] and inhibited both systemic and adipose tissue inflammation in HIV-positive people with impaired glucose tolerance [19].…”

Section: Introductionmentioning

confidence: 99%

Effects of saxagliptin on adipose tissue inflammation and vascular function in overweight and obese people: a placebo‐controlled study

et al. 2019

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Aims To test the effect of the dipeptidyl peptidase‐4 inhibitor saxagliptin on adipose tissue inflammation and microvascular function, and whole‐body postprandial endothelial function. Methods A randomized, double‐blind, placebo‐controlled, parallel study was conducted between June 2013 and November 2016 in 44 overweight or obese people without diabetes (saxagliptin, n=28; placebo, n=16). Subcutaneous abdominal adipose tissue biopsies, a 4‐h fat‐enriched meal test and peripheral arterial tonometry for measurement of endothelial function were performed at baseline and after 6 weeks of treatment with saxagliptin (5 mg/day) or matching placebo. Results Forty participants were analysed (saxagliptin, n=26; placebo, n=14). Secretion of interleukin‐8 from adipose tissue explants was reduced after saxagliptin (median fold‐change from baseline: 0.8 saxagliptin vs 3.3 placebo; P=0.02). Adipose tissue expression of thioredoxin‐inhibitory protein (TxNIP) was lower after saxagliptin (0.75 vs 1.0; P=0.02), while there were no significant differences in adipose tissue secretion of interleukin‐1b, interleukin‐6 or macrophage chemoattractant protein 1 (MCP‐1), adipose tissue macrophage content, adipose tissue mRNA levels of mcp1, cd36, cd68, il6, il8, txnip and adpq, and activation of adipose tissue inflammatory pathways [extracellular signal‐regulated kinase, c‐Jun N‐terminal kinase (JNK) and nuclear factor‐κB (NF‐ κB)] or insulin‐induced vasodilation of adipose tissue arterioles. Postprandial plasma glucose was slightly lower (by an estimated 0.3 mmol/l; P=0.01), while postprandial insulin, triglyceride levels and endothelial function were unchanged after saxagliptin. Conclusions The effect of saxagliptin on adipose tissue inflammation was relatively modest, with many inflammatory markers unchanged. We also found no evidence that saxagliptin therapy improved adipose tissue arteriole vasodilation or postprandial endothelial function.

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“…A randomized open label control study showed that the combination of sitagliptin, a dipeptidyl peptidase-4 inhibitor, with ultraviolet phototherapy improved psoriasis more effectively than phototherapy alone 26 . Another observational study reported that sidagliptin decrease inflammation in HIV infection 27 . Also metformin ameriorates disease activity in CIA mice and IBD mice 28 29 .…”

Section: Discussionmentioning

confidence: 99%

3-bromopyruvate ameliorate autoimmune arthritis by modulating Th17/Treg cell differentiation and suppressing dendritic cell activation

Okano

Saegusa

Nishimura

et al. 2017

Sci Rep

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Recent studies have shown that cellular metabolism plays an important role in regulating immune cell functions. In immune cell differentiation, both interleukin-17-producing T (Th17) cells and dendritic cells (DCs) exhibit increased glycolysis through the upregulation of glycolytic enzymes, such as hexokinase-2 (HK2). Blocking glycolysis with 2-deoxyglucose was recently shown to inhibit Th17 cell differentiation while promoting regulatory T (Treg) cell generation. However, 2-DG inhibits all isoforms of HK. Thus, it is unclear which isoform has a critical role in Th17 cell differentiation and in rheumatoid arthritis (RA) pathogenesis. Here we demonstrated that 3-bromopyruvate (BrPA), a specific HK2 inhibitor, significantly decreased the arthritis scores and the histological scores in SKG mice, with a significant increase in Treg cells, decrease in Th17 cells, and decrease in activated DCs in the spleen. In vitro, BrPA facilitated the differentiation of Treg cells, suppressed Th17 cells, and inhibited the activation of DCs. These results suggested that BrPA may be a therapeutic target of murine arthritis. Although the role of IL-17 is not clarified in the treatment of RA, targeting cell metabolism to alter the immune cell functions might lead to a new therapeutic strategy for RA.

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Sitagliptin Reduces Inflammation and Chronic Immune Cell Activation in HIV+ Adults With Impaired Glucose Tolerance

Abstract: Sitagliptin had beneficial systemic and adipose anti-inflammatory effects in cART-treated HIV+ adults with impaired glucose tolerance. Large-scale, long-term studies should determine whether sitagliptin reduces cardiovascular risk and events in HIV+ adults.

Cited by 34 publications

References 37 publications

Feasibility of quantifying change in immune white cells in abdominal adipose tissue in response to an immune modulator in clinical obesity

Feasibility of quantifying change in immune white cells in abdominal adipose tissue in response to an immune modulator in clinical obesity

Effects of saxagliptin on adipose tissue inflammation and vascular function in overweight and obese people: a placebo‐controlled study

3-bromopyruvate ameliorate autoimmune arthritis by modulating Th17/Treg cell differentiation and suppressing dendritic cell activation

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