Ischemic Injury and Ischemic Preconditioning in Diabetes

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.

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).

• Diabetes Mellitus, Insulin-Dependent
• Ischemia-Reperfusion Injury

• Procedure: Ischemic preconditioning
• Procedure: Forearm ischemic exercise
• Procedure: Annexin A5 scintigraphy
• Drug: Diazoxide
• Drug: glibenclamide
• Drug: adenosine

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