Sitagliptin and Brown Adipose Tissue

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.

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)