The investigators will assess whether the DPP-inhibitor sitagliptin will ameliorate glucocorticoid-induced impairment of glucose metabolism and beta-cell dysfunction and thus could be used as a prophylaxis for glucocorticoid-induced diabetes. Therefore the investigators will administer in males with the metabolic syndrome 30 mg prednisolone daily for two weeks and give simultaneously sitagliptin 100 mg daily. Subjects will undergo at baseline and after two weeks of treatment several tests to assess changes in glucose metabolism.

The investigators will conduct a randomized, placebo-controlled, double-blind, 2x2 factorial-designed intervention trial. The pharmacological intervention for prednisolone/prednisolone-placebo is 14 days and for sitagliptin/sitagliptin-placebo 28 days. Subjects fulfilling the IDF criteria26 for the metabolic syndrome (aged 35-65; n=60) will be randomized to one of four groups: I) prednisolone 30 mg and sitagliptin 100 mg daily; II) prednisolone 30 mg and sitagliptin-placebo daily; III) prednisolone-placebo and sitagliptin 100 mg daily; IV) prednisolone-placebo and sitagliptin-placebo daily. Before and at day 14 of treatment subjects will undergo a standardized mixed-meal test in order to assess glucose disposal and beta-cell function (by modeling analysis). During these meal tests, plasma concentrations of (total and active) GLP-1, GIP, glucagon and additional biomarkers will be assessed. A combined hyperglycemic-euglycemic clamp will be performed at baseline and at day 13 of treatment to assess insulin sensitivity and insulin secretion. During the euglycemic clamp adipose tissue and muscle biopsies will be obtained, both in fasting and under hyperinsulinemic conditions. At baseline and at day 28 of treatment, a 7-point OGTT will be performed to assess time to restoration of glycemic control. Body composition, body fat distribution and liver fat content, measured by respectively bio-impedance analysis and magnetic resonance imaging/spectroscopy (MRI/MRS), will be assessed at baseline and after 28 days of treatment. Blood pressure will be assessed at baseline and after two weeks of treatment. Microvascular function will be assessed with capillary videomicroscopy both at baseline and after two weeks of treatment.

Inclusion Criteria:

• Caucasian males

• Modified from IDF criteria for the metabolic syndrome:

  • Waist circumference ≥ 94 cm

• And at least 2 or more of the following criteria:

  • TG ≥ 1.7 mmol/L
  • HDL cholesterol < 1.03 mmol/L
  • Blood pressure >130/85 mmHg (average of three measurements) or treatment of previously diagnosed hypertension
  • Fasting plasma glucose level (FPG) ≥ 5.6 mmol/L (but no diabetes)

Exclusion Criteria:

• An allergic or anaphylactic reaction to prednisolone treatment in the past
• Clinically relevant history or presence of any medical disorder, which are mentioned in the Summary of Product Characteristics (SPC) as contraindication for the use of prednisolone
• Glucocorticosteroid use during the last three months prior to the first dose
• Participation in an investigational drug trial within 90 days prior to the first dose
• Donation of blood ( > 100 mL) within 90 days prior to the first dose
• History of or current abuse of drugs or alcohol (>14 U/week)
• Use of grapefruit products during the study period
• Recent changes in weight and/or physical activity
• Serious mental impairment or language problems i.e. preventing to understand the study protocol/aim
• Diabetes mellitus (defined as FPG ≥ 7.0 mmol/l and/or 2hPG ≥ 11.1 mmol/l)
• Serious pulmonary, cardiovascular, hepatic (ALT, AST more than 3x ULN) or renal disease (serum creatinine > 135 micromol/L)
• History of cardiovascular disease, such as myocardial infarction, cerebrovascular accident.
• Major psychiatric disorder, depression
• All diseases that induce changes in the hypothalamic-pituitary-adrenal (HPA) axis
• Malignant disease
• All other relevant medical disorders that potentially interfere with this trial.
• All medication interfering with study drug or interfering with study endpoints/hypotheses