Clinical Trial: Sitagliptin and Brown Adipose Tissue

Study Status: Recruiting
Recruit Status: Recruiting
Study Type: Interventional

Official Title: The Effect of Sitagliptin on Brown Adipose Tissue and Whole-body Metabolism in Overweight Pre-diabetic Men

Brief 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

Detailed Summary:

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
Sponsor: IngridJazet

Current Primary Outcome: The effect of sitagliptin treatment on BAT activity in overweight, pre-diabetic subjects BAT volume and activity will be measured by means of cold-induced 18F-FDG PET-CT scans [ Time Frame: after 12 weeks of treatment ]

Original Primary Outcome: Same as current

Current Secondary Outcome:

• The effect of sitagliptin treatment on energy expenditure in overweight, pre-diabetic subjects indirect calorimetrie [ Time Frame: after 12 weeks of treatment ]
  indirect calorimetrie
• The effect of sitagliptin treatment on muscle glucose metabolism in overweight, pre-diabetic subjects Expression and/or activation of biomarkers for insulin signaling and glucose and lipid metabolism in skeletal muscle biopsies [ Time Frame: after 12 weeks of treatment ]
  Expression and/or activation of biomarkers for insulin signaling and glucose and lipid metabolism in skeletal muscle biopsies
• The effect of sitagliptin treatment on fat mass in overweight, pre-diabetic subjects Fat mass will be measured via DEXA scan [ Time Frame: after 12 weeks of treatment ]
  Fat mass will be measured via DEXA scan
• The effect of sitagliptin treatment on glucose metabolism in overweight, pre-diabetic subjects serum glucose, insulin, and HbA1c. Furthermore, insulin secretion will be determined by OGTT together with C-peptine, glucose and insulin area under the curve [ Time Frame: after 12 weeks of treatment ]
  We will assess fasting serum glucose, insulin, and HbA1c. Furthermore, insulin secretion will be determined by OGTT together with C-peptine, glucose and insulin area under the curve
• The effect of sitagliptin treatment on plasma lipid levels in overweight, pre-diabetic subjects total cholesterol, HDL-C LDL-C triglycerides, and free fatty acids in plasma [ Time Frame: after 12 weeks of treatment ]
  We will assess total cholesterol, HDL-C LDL-C triglycerides, and free fatty acids in plasma

Original Secondary Outcome: Same as current

Information By: Leiden University Medical Center

Dates:
Date Received: November 17, 2014
Date Started: March 2014
Date Completion: November 2016
Last Updated: March 24, 2016
Last Verified: March 2016