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Elevated Pregnancy-Associated Plasma Protein-A in Sera from Type 2 Diabetic Patients with Hypercholesterolemia: Associations with Carotid Atherosclerosis and Toe-Brachial Index

Department of Internal Medicine (Y.A., K.-I.O., S.W., K.T., T.I.), Koshigaya Hospital, Dokkyo University School of Medicine, Saitama 343-8555, Japan; and Testing Department D (S.T.), Metabolism and Endocrinology Group, Mitsubishi Kagaku Bio-Clinical Laboratories Inc., Tokyo 174-8555, Japan

Address all correspondence and requests for reprints to: Yoshimasa Aso, M.D., Department of Internal Medicine, Dokkyo University School of Medicine, Koshigaya Hospital, 2-1-50 Minami-Koshigaya, Koshigaya, Saitama 343-8555, Japan. E-mail: yaso{at}dokkyomed.ac.jp.

Pregnancy-associated plasma protein (PAPP)-A, a superfamily of metalloproteinase, has been implicated in acute coronary syndrome. We compared PAPP-A concentrations in sera from patients with type 2 diabetes with those in sera from age-matched control subjects and also investigated whether serum PAPP-A was associated with carotid intima-media wall thickness (IMT), an early marker of atherosclerosis, and indices of peripheral vascular disease in the diabetic patients. Serum PAPP-A was measured by an ELISA in 103 type 2 diabetic patients and 32 age-matched control subjects. All subjects were not pregnant. IMT was evaluated ultrasonographically in both common carotid arteries. As measures of peripheral vascular disease, we also determined the ankle-brachial index and toe-brachial index (TBI) for systolic blood pressure. Hypercholesterolemia was defined as a serum low-density lipoprotein-cholesterol concentration exceeding 3.6 mmol/liter or alternatively as a treatment with hydroxymethylglutaryl coenzyme A reductase inhibitor. Serum PAPP-A was significantly higher in diabetic patients than control subjects (P < 0.0001). In diabetic patients, serum PAPP-A correlated positively with serum total cholesterol (r = 0.289, P = 0.0041) and IMT (r = 0.315, P = 0.0017) and negatively with TBI (r = –0.294, P = 0.0039) but not ankle-brachial index. Diabetic patients with hypercholesterolemia had higher PAPP-A concentrations than those without hypercholesterolemia [median (interquartile ranges): 8.37 (6.93, 11.6) vs. 7.29 (5.65, 9.21) mIU/liter; P = 0.0209]. Multivariate analysis identified only serum total cholesterol as an independent determinant of serum PAPP-A in patients with type 2 diabetes (partial coefficient 0.454, P = 0.020). In conclusion, serum PAPP-A concentrations were significantly elevated in diabetic patients with hypercholesterolemia and were associated positively with carotid atherosclerosis and negatively with TBI in type 2 diabetes.

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