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Fibrinolytic System During Long-Distance Running in IDDM Patients and in Healthy Subjects BERT-JAN POTTER VAN LOON, MD LEO P. HEERE, MD CORNELIUS KLUFT, PHD

ERNEST BRIET, MD, PHD GERARD DOOIJEWAARD, PHD AREND E. MEINDERS, MD, PHD

OBJECTIVE — Endurance exercise has been advocated in diabetes mellitus to improve both metabolic control and prevent atherosclerotic complications. The response of the fibrinolytic system during prolonged exercise has not been studied in diabetes. RESEARCH DESIGN AND METHODS— In seven male marathon runners with IDDM and eight healthy nondiabetic male control subjects, matched for age and degree of training, we studied fibrinolytic and coagulation parameters during a 3-h 32-km outdoor running session. Measurements included t-PA, u-PA, PAI-1, PAP (as a measure of in vivo activation of fibrinolysis), FbDPs, FGN, vWF, and VII1:C. RESULTS— In both IDDM and control subjects, levels of t-PA, u-PA, PAP, vWF, and VIILC continued to rise throughout the exercise, whereas PAl-1 showed a similar decline in both groups. FbDP rose slightly in both groups, and FGN remained unchanged. t-PA levels during exercise correlated closely with exercise intensity. These findings indicate that continued stimulation by exercise does not deplete endothelial PA stores. Differences between IDDM and control subjects were seen only for t-PA, vWF, and u-PA. The AUC during exercise (AUC05_30) of t-PA in IDDM was insignificantly lower than in control subjects (53 ± 19 vs. 67 ± 31 ng • ml" 1 • h), but the ratio of t-PA to exercise intensity was lower in IDDM (0.24 ± 0 . 1 1 vs. 0.31 ± 0.13, P < 0.05). The AUC 05 _ 3 0 of vWF was lower in IDDM than in control subjects (569 ± 268 vs. 880 ± 265 % • h, P < 0.05). The AUC0 5 _ 3 0 of u-PA was higher in IDDM than in control subjects (15.1 ± 3.5 vs. 11.2 ± 1.8 ng • ml" 1 • h, P < 0.05). CONCLUSIONS — Despite a defect in the exercise-induced endothelial release of vWF and t-PA, the overall potential to activate fibrinolysis is intact in IDDM, possibly by enhancement of u-PA after exercise. Our data suggest that in IDDM, as in nondiabetic subjects, long-distance running may slow the progression of atherosclerosis by stimulating fibrinolysis.

FROM THE DEPARTMENT OF INTERNAL MEDICINE, UNIVERSITY HOSPITAL, LEIDEN; THE DEPARTMENT OF SPORTS MEDICINE, NETHERLANDS SPORTS FEDERATION, ARNHEM; AND THE GAUBIUS LABORATORY, TNO,

IWO-

LEIDEN, NETHERLANDS.

ADDRESS CORRESPONDENCE AND REPRINT REQUESTS TO BERT-JAN POTTER VAN LOON, MD, DEPARTMENT OF INTERNAL MEDICINE, SINT LUCAS ZIEKENHUIS, JAN TOOROPSTRAAT 1 6 4 , 1 0 6 1 A E AMSTERDAM, NETHERLANDS. RECEIVED FOR PUBLICATION 2 AUGUST 1991

AND ACCEPTED IN REVISED FORM 22 DECEMBER

1991.

I D D M , INSULIN-DEPENDENT DIABETES MELLITUS; T-PA, TISSUE-TYPE PLASMINOGEN ACTIVATOR; U-PA, UROKINASE-TYPE

PLASMINOGEN

ACTIVATOR;

P A L - 1 , PLASMINOGEN

ACTIVATOR INHIBITOR TYPE 1;

PAP,

PLASMIN-a2 ANT1PLASM1N COMPLEX; F B D P , FIBRIN DEGRADATION PRODUCT; F G N , INTACT F1BRINOGEN; V W F , VON WlLLEBRAND FACTOR; V I I L C , COAGULATION FACTOR V l l l ; A U C , AREA UNDER THE CURVE; E M H R , ESTIMATED MAXIMAL HEART FREQUENCY; R M - A N O V A , REPEATED-MEASURES ANALYSIS OF VARIANCE.

DIABETES CARE, VOLUME 15,

NUMBER 8, AUGUST

1992

atients with diabetes mellitus are reported to have a twofold higher incidence of coronary artery disease and a threefold higher incidence of peripheral arterial disease compared with nondiabetic subjects matched for other cardiovascular risk factors (1). A decrease in plasma fibrinolytic activity may play a role in the pathogenesis of atherosclerotic complications (2,3) by reducing degradation of fibrin. Plasma fibrinolytic activity is determined by the balance between PAs and their inhibitors. In the basal state, activators are mostly bound to PAI-1, and the resultant fibrinolytic activity is low (4). After stimuli such as exercise, venous occlusion, or infusion with l-desamino-8-D-arginine vasopressin, fibrinolytic activity increases due to the endothelial release of t-PA and u-PA (5-7). Studies in IDDM have demonstrated an impaired t-PA response to exercise in subjects with microalbuminuria and proteinuria but not in normoalbuminuric patients (8). However, the stimulus for t-PA release was only of short duration.

Endurance exercise has been advocated in the treatment of diabetes for both improvement of metabolic control (9,10) and prevention of atherosclerotic complications (11). We previously reported on the metabolic effects of prolonged exercise in IDDM subjects (12). Repeated bouts of exercise may result in a blunted t-PA response (13), and it has been suggested that the endothelium becomes depleted of t-PA after repeated stimulation (14,15), because prolonged exercise might adversely affect fibrinolysis. Furthermore, the finding of a blunted response to repeated exercise suggests that prolonged exercise may be a sensitive test to uncover defects in the release of PAs. In diabetes mellitus, however, prolonged continuous stimulation of the fibrinolytic system has not been studied. We studied seven well-trained IDDM marathon runners without micro- or macroalbuminuria. Herein, we report on the response of the fibrinolytic system to prolonged exercise in IDDM and nondi-

991

Fibrinolysis in long-distance running in IDDM

abetic control subjects during a 32-km 3-h outdoor running session.

RESEARCH DESIGN AND METHODS— Seven men with IDDM and adequate metabolic control and eight healthy nondiabetic men matched for age and degree of training participated in the study after giving informed consent. The study protocol was approved by the ethics committee of the University Hospital, Leiden. All subjects ran a complete marathon within 3.5 h. All diabetic subjects were C-peptide negative, had grade 0-1 retinopathy at most, and had a normal albumin excretion (albumin-creatinine ratio in morning urine