Clinical trial NCT00184821: Ischemic Injury and Ischemic Preconditioning in Diabetes
Official title: Acute Local Ischemic Preconditioning in Patients With Type 1 Diabetes in Vivo
Study type: OBSERVATIONAL
Overall status: COMPLETED
Conditions: Diabetes Mellitus, Insulin-Dependent
Ischemia-Reperfusion Injury
Keywords: Diabetes
Ischemia
Annexin A5 scintigraphy
Lead sponsor: Radboud University Medical Center
Sponsor class: OTHER
Collaborators: name: Dutch Diabetes Fund
First posted: 2005-09-16
Enrollment: 20
Sex: ALL
Minimum age (years): 18
Maximum age (years): 50
Standard ages: ADULT
Accepts healthy volunteers: no
Observational model: DEFINED_POPULATION
Time perspective: OTHER

Brief summary: In this proof-of-concept study, forearm vulnerability to ischemic exercise is studied in patients with type 1 diabetes mellitus with and without prior ischemic preconditioning (short period of ischemia that protects against subsequent ischemic exercise). Annexin A5 scintigraphy is used to quantify subtle signs of mild and reversible forearm injury that results from ischemic exercise.

The following hypotheses are tested:

1. Patients with type 1 diabetes are not more vulnerable to ischemic injury as compared with previously studied healthy volunteers.
2. Ischemic preconidtioning is still present in patients with type 1 diabetes. Depending on the validity of hypothesis 2, the effect of short pharmacological interventions are studied on vulnerability to forearm ischemia/reperfusion injury in the absence or presence of local forearm ischemic preconditioning.

Detailed description: All patients will be studied in supine position after an overnight fast, while plasma glucose levels are monitored. In the first 8 patients intravenous insulin is administered as needed, to reach target glucose levels between 5-7 mmol/l. Patients will be subjected to 10 minutes of forearm ischemia (non-dominant arm), combined with handgripping at 50% of maximal force until exhaustion. Upon reperfusion, Tc-99m-HYNIC-Annexin A5 will be injected intravenously. Targeting of annexin A5 to thenar muscle and forearm flexor muscle will be quantified as the percentage difference in radioactivity between experimental and control side. This procedure will be performed twice (randomized cross-over design), with at least 2 week interval, either with or without 10 minutes ischemia followed by 10 minutes of reperfusion prior to ischemic exercise.

Depending on the results of this study, substudies will be performed to study the effect of diazoxide (K-ATP channel opener, may mimic ischemic preconditioning), glibenclamide (K-ATP channel blocker, may inhibit ischemic preconditioning) or adenosine (infusion into brachial artery of non-dominant arm as a substitute for ischemic preconditioning).

Eligibility criteria: Inclusion Criteria:

* type 1 diabetes mellitus
* age 18-50 years

Exclusion Criteria:

* hypertension (systolic blood pressure \> 140 mmHg and/or diastolic blood pressure \> 90 mmHg
* cardiovascular disease (coronary artery insufficiency,CVA/TIA, peripheral artery disease
* HbA1c \> 9%
* Body Mass Index \< 25 kg/m2
* Unable to stop co-medication (other than insulin) for 1 week
* Previous exposure to radiation (diagnostic or therapeutic) in the past year

Primary outcomes:
Secondary outcomes:
Other outcomes:
Locations:
city: Nijmegen
country: Netherlands
facility: Clinical Research Centre Nijmegen; Radboud University Nijmegen Medical Centre
state: Gelderland
Study officials:
affiliation: Radboud University Nijmegen Medical Centre; department of Pharmacology-Toxicology
name: Richard Engbersen, MD
role: STUDY_CHAIR
affiliation: Radboud University Nijmegen Medical Centre; Department of Pharmacology-Toxicology
name: Gerard Rongen, MD, PhD
role: STUDY_CHAIR
affiliation: Radboud University Nijmegen Medical Centre; Department of Nuclear Medicine
name: Wim Oyen, MD, PhD
role: STUDY_CHAIR
affiliation: Canisius Wilhelmina Ziekenhuis Nijmegen; Department of Internal Medicine
name: Marc Mol, MD, PhD
role: STUDY_CHAIR
affiliation: Radboud University Nijmegen Medical Centre; Department of Pharmacology-Toxicology
name: Paul Smits, MD, PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: Catharina Hospital Eindhoven, Dept. of Internal Medicine
name: B. Bravenboer, MD, PhD
role: STUDY_CHAIR
References:
citation: Engbersen R, Riksen NP, Mol MJ, Bravenboer B, Boerman OC, Meijer P, Oyen WJ, Tack C, Rongen GA, Smits P. Improved resistance to ischemia and reperfusion, but impaired protection by ischemic preconditioning in patients with type 1 diabetes mellitus: a pilot study. Cardiovasc Diabetol. 2012 Oct 10;11:124. doi: 10.1186/1475-2840-11-124.