Sitagliptin and Brown Adipose Tissue
Condition: Neoplasms, Adipose Tissue
MeSH terms: Neoplasms, Adipose Tissue
Study type: Interventional
Phase: Phase 4

Summary: 
      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.
    

Detailed description: 
      In the current study, the effect of 12 weeks of STG treatment (100 mg/day p.o.) versus
      placebo will be studied in moderately obese pre-diabetic Dutch Caucasians males (35-50
      years).

      All study subjects will be screened and if the subject meets all the inclusion criteria, is
      willing to participate in the study and has signed the informed consent, he will be included.
      All subjects will be asked not to make any changes in their usual diets and physical
      activities before the start of the whole study. Subjects will undergo two study days (day 1
      and day 2) before STG or placebo treatment and two study days after treatment (day 84 and day
      85) on which a cold-induced PET-CT scan as well as metabolic studies and skeletal muscle
      biopsies are performed.

      At screening a thorough medical history (see Appendix D) and physical examination will be
      performed. Subjects will be examined while in the fasting state. Anthropometric measurements
      will be performed as well as a basal blood sample will be taken by means of a venapunction.
      Basal blood measurements include hematology and kidney, liver, thyroid and lipid parameters
      as well as glucose, C-peptide and insulin concentrations. Thereafter, subjects ingest 75
      grams of glucose orally (t=0) and at t=120 minutes a blood sample for the determination of
      glucose, C-peptide and insulin will be drawn (venapunction) to assess glucose tolerance.

      On study days 1 and 84, which take place at the dept. of Nuclear Medicine in the Rijnland
      hospital, anthropometric measurements will be performed first, followed by ingestion of a
      CoreTemp Pill for core temperature registration application, a DEXA scan, and application of
      wireless iButtons to monitor skin temperature. Next, subjects will lay in a bed between two
      water-perfused matrasses and water temperature will be set at 32°C (= thermoneutrality).
      After 30 min of thermoneutrality, resting energy expenditure (REE) will be measured via
      ventilated hoods. Then, thermoneutral venous blood samples will be obtained. Water
      temperature will be gradually decreased and stabilized just above shivering level to induce
      maximum non-shivering thermogenesis (NST) for the next two hours. During the cooling period,
      blood pressure, heart rate and shivering are monitored at fixed intervals. At t=60 min, after
      one hour of stable cooling, 110 MBq (2.09 mSv) 18F-fluorodeoxyglucose (FDG) will be injected.
      At t=90 min, REE will be measured again. At t=120 min, cold-induced venous blood samples will
      be obtained followed by performance of the PET-CT scan (see Appendix B for an overview of
      study days 1 and 84).

      On study days 2 and 85, which will be performed at the research laboratory at the LUMC, a
      muscle biopsy will be taken first. Then, after 1 hour of rest, an OGTT will be performed. To
      this end, a glucose drink containing 75 g of glucose will be ingested in maximum 5 minutes
      and at t=-10, 0, 10, 20, 30, 40, 50, 60, 90 and 120 min venous samples will be taken to
      assess glucose, insulin and C-peptide levels (see Appendix C for an overview of study days 2
      and 85).

      During the treatment period, study subjects will be called weekly by the researcher to ask
      for possible side effects, signs of hypoglycemia, plasma glucose levels (via finger prick,
      which will be done by the study subject himself) and compliance. Once a month, the study
      subject will return to the research laboratory at the LUMC. During this occasion, next to the
      above-mentioned parameters, also a venous blood sample will be obtained (venapunction) to
      assess plasma glucose, insulin and triglyceride levels.
    

Intervention name(s): Sitagliptin; placebo
Intervention type(s): Drug; Drug
Intervention description(s): Each subject in this arm will receive Sitagliptin (100mg/day) for a duration of 12 weeks.; Each subject will receive a placebo (once a day) for 12 weeks.
Other intervention name(s): Januvia
Intervention MeSH terms: Sitagliptin Phosphate
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Double (Participant, Investigator)
Primary purpose: Treatment