Sitagliptin and Brown Adipose Tissue

The obesity epidemic has resulted in an exponential increase in obesity-related disorders including type 2 diabetes, dyslipidemia and cardiovascular disease. The associated morbidity and mortality have major consequences both at an individual as well as on the socioeconomical level. Thus, the development of novel therapies aimed at reducing the development of obesity is highly warranted. Brown adipose tissue (BAT) recently emerged as a novel player in energy expenditure in humans as it combusts fatty acids towards heat. Interestingly, obese subjects have less BAT as compared to lean subjects and activation of BAT by means of intermittent cold exposure reduces fat mass. Therefore, BAT is considered a promising novel target to reduce obesity and associated disorders. As cold exposure is not the most desired therapeutic strategy for humans, current pre-clinical research focuses on pharmacological activation of BAT. Interestingly, the investigators have recently shown that central agonism of the receptor for the incretin hormone glucacon-like peptide-1 (GLP-1) results in activation of BAT in mice. One of the currently used anti-diabetic drugs that enhances GLP-1 availability is Sitagliptin (STG). Interestingly, STG also reduces body weight and plasma triglyceride (TG) levels in type 2 diabetes mellitus (T2DM) patients. The mechanism underlying these beneficial metabolic effects is currently unknown. The investigators hypothesize that STG enhances BAT activation, thereby increasing energy expenditure and combustion of TG-derived fatty acids, resulting in lowering of plasma TG levels and body weight. To this end, the investigators will perform a randomized double-blinded placebo-controlled study in which 30 male Dutch Caucasian adults aged 35-50 years with moderate obesity and pre-diabetes are included. Subjects will be treated for 12 weeks with STG or placebo. Before and after treatment, the investigators will determine BAT volume and total BAT activity via cold-induced 18F-FDG PET-CT scans, resting energy expenditure via indirect calorimetry using ventilated hoods, body weight, and body composition via DEXA scan. Furthermore, before and after treatment, blood samples will be taken to measure plasma lipids, glucose and insulin levels. This study will offer valuable novel insight in the effects of pharmacological activation of BAT in human obese subjects.

Sex

Male

Minimum age

35 Years

Maximum age

50 Years

Inclusion Criteria:

* Male volunteers, Caucasians, born in the Netherlands
* Age: 35-55 years
* BMI \> 25 and \< 32 kg/m2
* plasma glucose levels 2 h after OGTT between 7.8 and 11 mM (e.g. impaired glucose tolerance)

Exclusion Criteria:

* Diabetes mellitus (determined on basis of oral glucose tolerance test (OGTT)) defined by ADA criteria
* BMI \> 30 kg/m2 or \< 25 kg/m2
* plasma glucose levels 2 h after OGTT \< 7.8 or \> 11.1 mM
* use of medication known to influence glucose and/or lipid metabolism or BAT activity (e.g. beta blockers)
* any significant chronic disease
* renal, hepatic or endocrine disease
* smoking
* participation in an intensive weight-loss program or vigorous exercise program during the last year before start of the study
* difficulties to insert an intravenous catheter
* recent participation in other research projects (within the last 3 months)

• DERIVEDNahon KJ, Doornink F, Straat ME, Botani K, Martinez-Tellez B, Abreu-Vieira G, van Klinken JB, Voortman GJ, Friesema ECH, Ruiz JR, van Velden FHP, de Geus-Oei LF, Smit F, Pereira Arias-Bouda LM, Berbee JFP, Jazet IM, Boon MR, Rensen PCN. Effect of sitagliptin on energy metabolism and brown adipose tissue in overweight individuals with prediabetes: a randomised placebo-controlled trial. Diabetologia. 2018 Nov;61(11):2386-2397. doi: 10.1007/s00125-018-4716-x. Epub 2018 Aug 25. PMID 30145664