Correlation Between Plasma- and Endothelial DPP-4 Activity

The investigators want to estimate both the endothelial and the plasma activity of dipeptidyl peptidase 4 during different doses of sitagliptin in healthy subjects and patients with type 2 diabetes. Furthermore, the investigators want to investigate whether the current clinical dose of 100 mg of sitagliptin is sufficient to inhibit both the plasma and the endothelial activity of the enzyme dipeptidyl peptidase 4.

The two incretin hormones glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) are secreted from the intestinal L- and K- cells, respectively in response to ingestion of nutrients. The two hormones are able to lower blood glucose levels during high glucose levels - by the so called incretin effect. GIP and GLP-1 are both rapidly inactivated by the enzyme dipeptidyl peptidase 4 (DPP-4). The remaining metabolites are without insulinotropic effects. The effect of DPP-4 inhibitors used in treatment of type 2 diabetes relies on their impact on DPP-4 activity. DPP-4 exists in a soluble form in plasma ad as a membrane-bound form in blood vessels and other tissues. The impact of DPP-4 inhibitors on DPP-4 activity has only been evaluated in plasma. We aim to investigate plasma and endothelial DPP-4 activity (i.e. whole-body DPP-4 activity) in patients with type 2 diabetes during different doses of the DPP-4 inhibitor sitagliptin. Both healthy control subjects and patients with type 2 diabetes are subjected to 4 experimental days (in a randomized order) with continuous infusion of GLP-1 and pre-treatment with 25 mg sitagliptin, 100 mg sitagliptin, 200 mg sitagliptin and placebo, respectively. Afterwards, we are going to measure the whole-body DPP-4 activity by comparing plasma levels of active (intact) GLP-1 and total GLP-1, and relate to plasma DPP-4 activity.

Diabetes Mellitus, Glucagon-like peptide 1, Dipeptidyl peptidase 4, Dipeptidyl peptidase 4 inhibitor, sitagliptin, Enzyme activity

Patients with Type 2 Diabetes Mellitus and healthy control subjects are given tablets of sitagliptin in either a dosage of 25, 100 or 200 mg tablet in 3 different days.

In randomized order: Day 1: tablet of 25 mg of sitagliptin + i.v. GLP-1 infusion Day 2: tablet of 100 mg of sitagliptin + i.v. GLP-1 infusion Day 3: tablet of 200 mg of sitagliptin + i.v. GLP-1 infusion

Correlation between the total and intact GLP-1 hormone during different doses of sitagliptin measured as total area under the curve (tAUC)

GLP.1 total and GLP-1 intact will be calculated based on blood samples at time points: -40,-30,-20,-10,0,10,20,30,40,50,60,75,90,105,120,150,180,240,300,360 on all days

GLP-1 will be measured at time points(minutes): -40,-30,-20,-10,0,10,20,30,40,50,60,75,90,105,120,150,180,240,300,360 on all days

Glucose will be measured at time points(minutes): -40,-30,-20,-10,0,10,20,30,40,50,60,75,90,105,120,150,180,240,300,360 on all days

Insulin will be measured at time points(minutes): -40,-30,-20,-10,0,10,20,30,40,50,60,75,90,105,120,150,180,240,300,360 on all days

Inclusion Criteria: Caucasians with diet and/or metformin treated patients with type 2 diabetes (diagnosed according to the criterias of the World Health Organization) Normal Hemoglobin Prior Informed Consent Exclusion Criteria: Nephropathy Liver disease Inflammatory bowel disease Pregnancy

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