Aims/hypothesis: The aim of this study was to evaluate the effect of sitagliptin on glucose tolerance, plasma lipids, energy expenditure and metabolism of brown adipose tissue (BAT), white adipose tissue (WAT) and skeletal muscle in overweight individuals with prediabetes (impaired glucose tolerance and/or impaired fasting glucose). Methods: We performed a randomised, double-blinded, placebo-controlled trial in 30 overweight, Europid men (age 45.9 ± 6.2 years; BMI 28.8 ± 2.3 kg/m2) with prediabetes in the Leiden University Medical Center and the Alrijne Hospital between March 2015 and September 2016. Participants were initially randomly allocated to receive sitagliptin (100 mg/day) (n = 15) or placebo (n = 15) for 12 weeks, using a randomisation list that was set up by an unblinded pharmacist. All people involved in the study as well as participants were blinded to group assignment. Two participants withdrew from the study prior to completion (both in the sitagliptin group) and were subsequently replaced with two new participants that were allocated to the same treatment. Before and after treatment, fasting venous blood samples and skeletal muscle biopsies were obtained, OGTT was performed and body composition, resting energy expenditure and [18F] fluorodeoxyglucose ([18F]FDG) uptake by metabolic tissues were assessed. The primary study endpoint was the effect of sitagliptin on BAT volume and activity. Results: One participant from the sitagliptin group was excluded from analysis, due to a distribution error, leaving 29 participants for further analysis. Sitagliptin, but not placebo, lowered glucose excursion (−40%; p < 0.003) during OGTT, accompanied by an improved insulinogenic index (+38%; p < 0.003) and oral disposition index (+44%; p < 0.003). In addition, sitagliptin lowered serum concentrations of triacylglycerol (−29%) and very large (−46%), large (−35%) and medium-sized (−24%) VLDL particles (all p < 0.05). Body weight, body composition and energy expenditure did not change. In skeletal muscle, sitagliptin increased mRNA expression of PGC1β (also known as PPARGC1B) (+117%; p < 0.05), a main controller of mitochondrial oxidative energy metabolism. Although the primary endpoint of change in BAT volume and activity was not met, sitagliptin increased [18F] FDG uptake in subcutaneous WAT (sWAT; +53%; p < 0.05). Reported side effects were mild and transient and not necessarily related to the treatment. Conclusions/interpretation: Twelve weeks of sitagliptin in overweight, Europid men with prediabetes improves glucose tolerance and lipid metabolism, as related to increased [18F] FDG uptake by sWAT, rather than BAT, and upregulation of the mitochondrial gene PGC1β in skeletal muscle. Studies on the effect of sitagliptin on preventing or delaying the progression of prediabetes into type 2 diabetes are warranted. Trial registration: NCT02294084. Funding: This study was funded by Merck Sharp & Dohme Corp, Dutch Heart Foundation, Dutch Diabetes Research Foundation, Ministry of Economic Affairs and the University of Granada.

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Keywords Brown adipose tissue, Diabetes risk, DPP4 inhibitor, Dyslipidaemia, Energy expenditure, Obesity, Prediabetes, Skeletal muscle
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Journal Diabetologia: clinical and experimental diabetes and metabolism
Nahon, K.J. (Kimberly J.), Doornink, F. (Fleur), Straat, M.E. (Maaike E.), Botani, K. (Kani), Martinez-Tellez, B. (Borja), Abreu-Vieira, G. (Gustavo), … Rensen, P.C.N. (2018). Effect of sitagliptin on energy metabolism and brown adipose tissue in overweight individuals with prediabetes: a randomised placebo-controlled trial. Diabetologia: clinical and experimental diabetes and metabolism. doi:10.1007/s00125-018-4716-x