Endocrine Abstracts

Introduction: Sirolimus, a mTOR (mechanistic Target of Rapamycin) inhibitor, is well known for its impact on glucides and lipids metabolism. These effects vary according to factors such as dose and treatment duration, species, cell types and environmental factors. In vitro and in vivo, sirolimus inhibits adipogenesis by decreasing adipocytes number and size, as well as pre-adipocytes differentiation, leading to subcutaneous and visceral fat mass decrease in murine models of obesity. Little is known on the long-term impact of sirolimus in human. We hypothesized that sirolimus could have a specific role on adipose tissue, possibly influencing islet transplantation prognosis. The aim of this study was to compare body composition and metabolic markers in 2 groups of islet–transplanted patients according to the immunosuppressive regimen including or not sirolimus.

Patients and Methods: We compared body composition and fat markers (weight, DEXA-fat and lean mass, and metabolic parameters) in two groups of non–obese islet-transplanted (ITA) patients treated (n=18) or not (n=13) with sirolimus, before and one year after islet transplantation for type 1 diabetes (T1D). Continuous variables were expressed as median (interquartile range [IQR]). ‘Sirolimus’ and ‘non-sirolimus’ groups were compared with a non-parametric Mann-Whitney test.

Results: Before transplantation, metabolic, renal and body composition parameters were similar in the 2 groups. Compared to baseline, we observed a significant decrease of weight (−6.3 kg (−9.67; −3.85), P=0.0131), BMI (−2.2 kg/m²(−3.17;−1.35), P=0.009), leptinaemia (−3.25 ng/ml (−7.6;−0.65), P=0.0103) and DEXA fat-mass(−5.5% (−10.7;−1.4), P=0.0384), after one year of treatment in the sirolimus-group, while there is no significant modificationt in the ‘non-sirolimus’ group. One-year after transplantation, weight, BMI, % of fat mass, metabolic and renal parameters did not differ between the 2 groups, except for leptinemia decrease of which was significantly higher in the ‘sirolimus’ vs. the ‘non-sirolimus’ group (P=0.008).

Conclusion: In non-obese T1D patients treated with sirolimus, islet-transplantation was associated with a significant fat loss, concomitant to metabolic improvement. Sirolimus exposure was also associated with a significant reduction of leptin as compared to ‘non-sirolimus’ islet –transplanted patients,. These findings could be related to the quality of adipose tissue, potentially modulating insulin resistance and innate immunity. On a broader scale, mTOR inhibitors, also used in the treatment of neuroendocrine tumors, could participate to crosstalk between cancer and immunity.