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.
Bone frailty is a relevant cause of morbidity and hospitalization in patients with T2D, however, its pathogenesis is not completely elucidated and specific strategies for preventing fractures in T2D patients are still lacking. Indeed, the novel data about a positive impact of DPP4-Is on bone health appear promising and worthy of further investigation. This project will explore the role of VD, active player in bone protection and immune-regulation, in mediating the effect of chronic DPP4-Is blockage on the skeleton. Our results will provide missing data on VD metabolism in the context of systemic and AT inflammation, condition likely exacerbated by DPP4 activation. We will describe the specific contribution of the DPP4 on VD status, inflammatory status and bone outcomes in T2D patients with or without chronic DPP4 blockage, and in comparison with metabolically-healthy obese subjects. This study, therefore, will provide novel and original evidence on the AT/inflammation/bone pathway in T2D and will improve knowledge on DPP4-Is non- glycaemic effects.