Effect of sitagliptin on energy metabolism and brown adipose tissue in overweight individuals with prediabetes: a randomised placebo-controlled trial

Abstract

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: ClinicalTrials.gov 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.

Keywords: Brown adipose tissue; DPP4 inhibitor; Diabetes risk; Dyslipidaemia; Energy expenditure; Obesity; Prediabetes; Skeletal muscle.

Conflict of interest statement

This work was supported in part by a research grant to PCNR from the Investigator Initiated Studies Program of Merck Sharp & Dohme Corp. The opinions expressed in this paper are those of the authors and do not necessarily represent those of Merck Sharp & Dohme Corp. The sponsor reviewed the report before publication. All other authors declare that there is no duality of interest associated with their contribution to this manuscript.

Figures

Fig. 1

The effect of sitagliptin on glucose tolerance in overweight men with prediabetes. An OGTT was performed to assess glucose tolerance, before (white circles and bars) and after (black circles and bars) 12 weeks of placebo (n = 15) or sitagliptin (n = 14) treatment. Serum was collected before and at several time points up to 120 min after ingestion of 75 g of glucose. Glucose and insulin excursions were determined at the indicated time points after treatment with placebo (a, d) or sitagliptin (b, e). Incremental AUC (AUCincr) was calculated for glucose (gluc; c) and insulin (ins; f). Data are presented as means ± SEM. Mixed model analysis was used for statistical comparison. In (a, b, d, e) *0.006 < p < 0.05 for week 0 vs week 12, not significant with Bonferroni-corrected level of significance 0.006 (α = 0.05/9). In (c, f) **p < 0.01 for week 0 vs week 12, significant with Bonferroni-corrected level of significance 0.01 (α = 0.05/4); ††p < 0.01 for placebo vs sitagliptin, significant with Bonferroni-corrected level of significance 0.01 (α = 0.05/4)

Fig. 2

The effect of sitagliptin on serum lipid and VLDL and HDL particle concentration in overweight men with prediabetes. Serum was collected before (week 0, white bars) and after (week 12, black bars) treatment with placebo (n = 15) or sitagliptin (n = 14). Enzymatic assays were used to measure serum triacylglycerol (TG) (a) and total cholesterol (TC) (b). HDL-cholesterol was determined by the general hospital laboratory of the LUMC (c) and LDL-cholesterol was calculated using the Friedewald equation (d). NMR was used to measure serum concentrations of extremely large (e), very large (f), large (g), medium-sized (h), small (i) and very small (j) VLDL particles, and very large (k), large (l), medium-sized (m) and small (n) HDL particles. In addition, mean VLDL (o) and mean HDL (p) particle size was determined. Data are presented as means ± SEM and as individual measurements. Mixed model analysis was used for statistical comparison. *0.003 < p < 0.05 for week 0 vs week 12, not significant with Bonferroni-corrected level of significance 0.003 (α = 0.05/16)

Fig. 3

The effect of sitagliptin on skeletal muscle gene expression in overweight men with prediabetes. A fasted skeletal muscle biopsy was taken before (white bars) and after (black bars) 12 weeks of treatment with placebo (n = 13) or sitagliptin (n = 11). qPCR was used to determine expression of genes involved in mitochondrial function, glucose metabolism and lipid metabolism, as well as DPP4 and FGF21, upon placebo (a, c) and sitagliptin (b, d) treatment. Data are presented as means ± SEM. Expression levels were normalised using the mRNA content of the housekeeping gene β-actin (ACTB) and expressed as fold change using the 2−ΔΔCt method. Mixed model analysis was used for statistical comparison. *0.002 < p < 0.05 for week 0 vs week 12, not significant with Bonferroni-corrected level of significance 0.002 (α = 0.05/21)