Clinical trial NCT02192853: Correlation Between Plasma- and Endothelial DPP-4 Activity
Official title: Plasma and Endothelial Activity of Dipeptidyl Peptidase 4 During Different Doses of Sitagliptin
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE4
Conditions: Type 2 Diabetes Mellitus
Keywords: Diabetes Mellitus
Glucagon-like peptide 1
Dipeptidyl peptidase 4
Dipeptidyl peptidase 4 inhibitor
sitagliptin
Enzyme activity
Lead sponsor: University Hospital, Gentofte, Copenhagen
Sponsor class: OTHER
First posted: 2014-07-17
Enrollment: 20
Sex: ALL
Minimum age (years): 35
Maximum age (years): 80
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: CROSSOVER
Primary purpose: TREATMENT

Brief summary: 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.

Detailed description: 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.

Eligibility criteria: 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

Primary outcomes:
measure: Correlation between the total and intact GLP-1 hormone during different doses of sitagliptin measured as total area under the curve (tAUC)
timeFrame: 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
Secondary outcomes:
measure: Differences in serum-/plasma concentrations of GLP-1 measured as total Area under the curve (tAUC)
timeFrame: 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
measure: Differences in glucose measured as total Area under the curve (tAUC)
timeFrame: 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
measure: Differences in Insulin measured as total Area under the curve (tAUC)
timeFrame: 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
Other outcomes:
Locations:
city: Hellerup
country: Denmark
facility: Diabetes Research Division, Department of Endocrinology, Gentofte Hospital
Study officials:
affiliation: Gentofte Hospital
name: Filip K Knop, MD PhD
role: STUDY_DIRECTOR
affiliation: Gentofte Hospital
name: Tina Vilsbøll, MD DMSc
role: STUDY_CHAIR
affiliation: Gentofte Hospital
name: Asger Lund, MD
role: STUDY_CHAIR
affiliation: Gentofte Hospital
name: Camilla Andersen, Med.stud.
role: STUDY_CHAIR
affiliation: Institute of biomedical sciences, University of Copenhagen
name: Jens Juul Holst, MD DMSc
role: STUDY_CHAIR
affiliation: Gentofte Hospital
name: Emilie Skytte Andersen, Med.stud.
role: PRINCIPAL_INVESTIGATOR
References:
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citation: Holst JJ. The physiology of glucagon-like peptide 1. Physiol Rev. 2007 Oct;87(4):1409-39. doi: 10.1152/physrev.00034.2006.
citation: Holst JJ, Vilsboll T, Deacon CF. The incretin system and its role in type 2 diabetes mellitus. Mol Cell Endocrinol. 2009 Jan 15;297(1-2):127-36. doi: 10.1016/j.mce.2008.08.012. Epub 2008 Aug 20.
citation: Orskov C, Wettergren A, Holst JJ. Biological effects and metabolic rates of glucagonlike peptide-1 7-36 amide and glucagonlike peptide-1 7-37 in healthy subjects are indistinguishable. Diabetes. 1993 May;42(5):658-61. doi: 10.2337/diab.42.5.658.
citation: Nauck MA, Heimesaat MM, Behle K, Holst JJ, Nauck MS, Ritzel R, Hufner M, Schmiegel WH. Effects of glucagon-like peptide 1 on counterregulatory hormone responses, cognitive functions, and insulin secretion during hyperinsulinemic, stepped hypoglycemic clamp experiments in healthy volunteers. J Clin Endocrinol Metab. 2002 Mar;87(3):1239-46. doi: 10.1210/jcem.87.3.8355.
citation: Gutzwiller JP, Drewe J, Goke B, Schmidt H, Rohrer B, Lareida J, Beglinger C. Glucagon-like peptide-1 promotes satiety and reduces food intake in patients with diabetes mellitus type 2. Am J Physiol. 1999 May;276(5):R1541-4. doi: 10.1152/ajpregu.1999.276.5.R1541.
citation: Vilsboll T, Krarup T, Madsbad S, Holst JJ. Both GLP-1 and GIP are insulinotropic at basal and postprandial glucose levels and contribute nearly equally to the incretin effect of a meal in healthy subjects. Regul Pept. 2003 Jul 15;114(2-3):115-21. doi: 10.1016/s0167-0115(03)00111-3.
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