DPP-4 activity in inflammation and bone metabolism: role of the DPP-4 in Vitamin D balance and bone health in relation to glucose metabolism and other metabolic complications of obesity
Dipeptidyl peptidase-4 inhibitors (DPP4-Is) represent a promising class of agents for type 2 diabetes (T2D) treatment. Recently, experimental models and clinical studies have reported positive effects of DPP4-Is on bone; however, how DPP4-Is positively impact bone homeostasis in humans remains an unanswered question. The DPP4 is a protein involved in many iinflammatory and endocrine pathways; its expression is increased in adipose tissue (AT) from obese subjects and DPP4-Is administration was shown to ameliorate AT inflammation in animal models. This project will test the hypothesis of a relationship between AT-DPP4 expression and vitamin D (VD) metabolism, as a link among DPP4- Is therapy and bone outcomes. AT not only represents the main site of VD accumulation in humans, but is also target of VD action. Thus, AT VD-hydroxylases may convert VD in its active forms which display autocrine and paracrine immunoregulatory actions through the specific VD receptor (VDR). Our preliminary data show the existence of a close relationship between DPP4-Is therapy and higher VD levels in T2D patients. It is plausible, indeed, that chronic DPP4 blockage modulates AT inflammation and stimulates VD activation and mobilization from adipocytes into the bloodstream. For testing this hypothesis, a total of 60 subjects candidate to bariatric surgery will be recruited: 20 T2D patients undertaking DPP4-Is during the previous 12 months, 20 T2D patients treated with other antidiabetic agents and 20 metabolically-healthy obese subjects. AT-VD activation (by CYP27A1, CYP27B1 and CYP2R1) and VDR expression will be evaluated in visceral AT biopsies in relation to AT-DPP4 expression and glucose tolerance; then we will investigate the relation between circulating/AT DPP4 levels, systemic VD balance and outcomes of bone metabolism. Indeed, this study will provide novel and original evidence on the AT/inflammation/bone pathway in T2D and add knowledge on non-glycaemic effects of DPP4-Is.