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

Abstract

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.

Plasma levels of DPP4 activity and sDPP4 are dissociated from inflammation in mice and humans

“…The rationale for development of DPP4 inhibitors for the therapy of T2D was largely based on findings that DPP4 inactivated GLP-1 and GIP, whereas inhibition of the enzyme stabilised levels of active incretin hormones and enhanced glucose homeostasis 1 , 3 , 47 , 48 . As inflammation is thought to underlie many of the complications associated with T2D, multiple studies have examined whether changes in inflammation arise following use of DPP4 enzyme inhibitors in the treatment of T2D 16 , 21 , 28 , 49 – 52 . Nevertheless, an emerging complementary literature, based predominantly on studies in cells and mice, has focused on the putative pro-inflammatory role of sDPP4 as an adipokine or hepatokine, independent of its catalytic activity 9 , 11 , 12 , 16 .…”

“…DPP4 inhibitors reduce pro-inflammatory cytokine production and immune cell infiltration in multiple tissues in both animals and humans [21][22][23][24][25][26] . On the other hand, several studies failed to detect an anti-inflammatory effect of DPP4 inhibitors in animals 27 or humans 28,29 . Surprisingly, sustained inhibition of DPP4 activity in mice was associated with elevations in levels of circulating sDPP4, a molecule with proinflammatory activity 16 , without evidence for increased inflammation 17 , raising further questions about the relationships between DPP4 activity, sDPP4 and inflammation.…”

Anti-inflammatory properties of antidiabetic drugs: A “promised land” in the COVID-19 era?

“… 77 Similarly, saxagliptin did not affect the secretion of IL-6 from adipocytes in 40 non-diabetic overweight/obese patients followed for 6 weeks. 78 No data on ferritin and saxagliptin exist.…”

The Emerging Role of TXNIP in Ischemic and Cardiovascular Diseases; A Novel Marker and Therapeutic Target

“…As reviewed elsewhere, glucose-induced higher tissue TXNIP expression has become a relevant therapeutic target not only to improve insulin secretion and sensitivity, but also for ameliorating the long-term microvascular and macrovascular complications of diabetes [67,145,[178][179][180][181]. As the first piece of evidence, commonly used antidiabetic therapies are associated with a decreased expression of TXNIP [91,[182][183][184][185][186], in particular via ChREBP and FOXO1 inactivation [121]. Indeed, endothelial dysfunction induced by high levels of TXNIP may have profound effects on the vasculature, a characteristic feature of metabolic disorders [13,20].…”