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Pregnancy-Associated Plasma Protein-A Levels Are Related to Glycemic Control but Not to Lipid Profile or Hemostatic Parameters in Type 2 Diabetes SILVIA PELLITERO, MD1 JORDI L. REVERTER, MD, PHD1 EDUARDA PIZARRO, MD, PHD2 MARIA CRUZ PASTOR, MD, PHD3 MARIA LUISA GRANADA, MD, PHD3

DOLORS TÀSSIES, MD, PHD4 JUAN-CARLOS REVERTER, MD, PHD4 ISABEL SALINAS, MD, PHD1 ANNA SANMARTÍ, MD, PHD1

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macrovascular disease, inflammatory disease, malignancies, or pregnancy were studied. Fifty-three (20 of whom were women) nondiabetic subjects without previous clinical macrovascular disease and normal ABI (ⱖ0.9) were recruited as control subjects. Demographic, anthropometric, and clinical data and ABI were recorded in all subjects. Laboratory data were measured by commercially available assays, hsCRP by nephelometry, ultrasensitive PAPP-A using an enzyme-linked immunosorbent assay, and TNF-␣ and IL-6 concentrations using an enzyme chemiluminescence immumometric assay. Continuous variables were expressed as means ⫾ SD or median (interquartile range). Differences between groups were examined by Student’s t test or MannWhitney and correlation between variables by Pearson’s or Spearman’s tests as required. Multiple logistic regression analysis was performed.

regnancy-associated plasma protein-A (PAPP-A) is a zinc-binding matrix metalloproteinase that regulates extracellular matrix remodeling. PAPP-A degrades IGFBP-4, increasing levels of local IGF-1 in response to injury, and could be involved in the pathogenesis of atherosclerosis (1– 6). Inflammatory cytokines tumor necrosis factor (TNF)-␣ and interleukin (IL)-1␤, implicated in insulin resistance (7), are potent stimulators of PAPP-A (8,9). The association between PAPP-A levels and metabolic parameters such as cholesterol and high-sensitivity C-reactive protein (hsCRP) is controversial (2,10,11). We aimed to study the relationship between PAPP-A, glycemic control and other metabolic and hemostatic parameters, inflammatory cytokines, and ankle-brachial pressure index (ABI) in diabetic patients. RESEARCH DESIGN AND METHODS — Type 2 diabetic patients (n ⫽ 175, 65 of whom were women) with stable glycemic control (variation in A1C ⬍10% in the last 5 years) and without diagnosis of clinical

RESULTS — Clinical and biochemical characteristics of all study subjects are shown in Table 1. PAPP-A levels were sig-

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From the 1Endocrinology and Nutrition Service, Department of Medicine, Germans Trias i Pujol University Hospital, Universitat Auto`noma de Barcelona, Badalona, Spain; the 2Endocrinology Unit, Mataro´ Hospital, Barcelona, Spain; 3Clinical Biochemistry Service, Germans Trias i Pujol University Hospital Universitat Auto`noma de Barcelona, Badalona, Spain; and the 4Hemotherapy and Hemostasis Service, Hospital Clinic, Barcelona, Spain. Address correspondence and reprint requests to Jordi L. Reverter, MD, PHD, Endocrinology and Nutrition Service, Germans Trias i Pujol University Hospital, Via Canyet s/n, 08916, Badalona, Spain. E-mail: [email protected]. Received for publication 8 June 2007 and accepted in revised form 21 August 2007. Published ahead of print at http://care.diabetesjournals.org on 28 August 2007. DOI: 10.2337/dc071092. Abbreviations: ABI, ankle-brachial pressure index; hsCRP, high-sensitivity C-reactive protein; IL, interleukin; PAPP-A, pregnancy-associated plasma protein-A; TNF, tumor necrosis factor. A table elsewhere in this issue shows conventional and Syste`me International (SI) units and conversion factors for many substances. © 2007 by the American Diabetes Association. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

DIABETES CARE, VOLUME 30, NUMBER 12, DECEMBER 2007

nificantly higher in male than in female subjects in both groups (median [interquartile range] 1.04 [0.6 –1.47] vs. 0.52 mIU/l [0.43– 0.94], P ⫽ 0.025 in control subjects and 0.49 [0.23– 0.93] vs. 0.35 mIU/l [0.13– 0.63], P ⫽ 0.01 in diabetic patients). Serum PAPP-A concentrations were significantly higher in control than in diabetic subjects (median [interquartile range] 0.73 [0.48 –1.33] vs. 0.45 mIU/l [0.19 – 0.82], respectively, P ⬍ 0.0001) and correlated negatively with A1C (r ⫽ ⫺0.2, P ⫽ 0.03). Diabetic patients were stratified according to mean ⫾ SD values of A1C (⬍5.9, 5.9 – 8.2, and ⬎8.2%). PAPP-A concentration was significantly lower in patients with A1C ⬎8.2% (0.35 mUI/l [0.07– 0.43]) compared with that in patients with A1C ⬍5.9% (0.72 mUI/l [0.2– 0.92], P ⬍ 0.03) and between 5.9 and 8.2% (0.56 mUI/l [0.15– 0.83], P ⬍ 0.02) and control subjects (0.73 mUI/l [0.48 –1.33], P ⬍ 0.001). No differences in PAPP-A levels were observed when subjects with normocholesterolemia were compared with those with hypercholesterolemia (median [interquartile range] 0.6 [0.45–1.14] vs. 0.8 mUI/l [0.48 –1.38], respectively) and with diabetic patients (0.6 [0.45–1.14] vs. 0.8 mUI/l [0.48 –1.38]). On the other hand, when control subjects and diabetic patients with normocholesterolemia were compared, PAPP-A levels remained significantly higher in control subjects than in diabetic patients (0.6 [0.45–1.14] vs. 0.33 mUI/l [0.13– 0.83], respectively, P ⫽ 0.04). We obtained the same results when control subjects and diabetic patients with hypercholesterolemia were compared (0.8 [0.48 –1.38] vs. 0.44 mUI/l [0.22– 0.78], P ⬍ 0.0001). Moreover, PAPP-A levels were similar in subjects treated with statins compared with those in untreated subjects in both groups. No differences were observed in PAPP-A levels between diabetic patients with or without a history of diabetic vasculopathy (n ⫽ 25), abnormal ABI (n ⫽ 54), nephropathy (n ⫽ 42), or retinopa3083

Pregnancy-associated plasma protein-A and diabetes Table 1—Clinical, biochemical, and hemostatic characteristics of control and diabetic subjects Control subjects n Male/female Age (years) Treatment (%) Antidiabetes drugs Insulin Combined Statins ABI ⬍0.9 Hypercholesterolemia Current smoker BMI (kg/m2) Waist circumference (cm) SBP (mmHg) DBP (mmHg) Fasting plasma glucose (mg/dl) A1C (%) Cholesterol (mg/dl) Total HDL Non-HDL Triglycerides (mg/dl) Uric acid (mg/dl) hsCRP (mg/l) Fibrinogen (g/l) F1 ⫹ 2 (nmol/l) PAP (␮g/l)

53 33/20 63.3 ⫾ 7.5

Diabetic patients 175 110/65 62 ⫾ 7.9

P — NS NS

— — — 27 — 69 19 29.5 ⫾ 2.6 98.7 ⫾ 7.9 149 ⫾ 19.5 87.6 ⫾ 9.3 81.3 ⫾ 11.9 5.2 ⫾ 0.9

39.3 27.7 34.0 70 30.8 84 17 31.1 ⫾ 4.7 104.3 ⫾ 11.8 146.7 ⫾ 20.7 79.1 ⫾ 11.4 156.2 ⫾ 46.9 7.1 ⫾ 1.1

— — — 0.001 — 0.02 NS 0.002 0.002 NS ⬍0.0001 ⬍0.0001 ⬍0.0001

210.6 ⫾ 39 48.3 ⫾ 13.6 162.2 ⫾ 34.5 97 (73–153) 5.1 ⫾ 1.5 3.47 (1.13–5.86) 3.2 ⫾ 1.0 0.81 ⫾ 0.32 198.9 ⫾ 90.2

182.3 ⫾ 39.7 44.8 ⫾ 13.6 136.5 ⫾ 36.8 131 (88–193) 5.8 ⫾ 1.6 3.15 (1.55–5.78) 4.5 ⫾ 1.1 2.03 ⫾ 0.65 207.1 ⫾ 87.3

⬍0.0001 NS ⬍0.0001 0.01 0.03 NS ⬍0.0001 ⬍0.0001 NS

Data are means ⫾ SD, percentages, or median (interquartile range). DBP, diastolic blood pressure; F1 ⫹ 2, prothrombin fragment 1 ⫹ 2; NS, nonsignificant; PAP, plasmin-antiplasmin complexes; SBP, systolic blood pressure.

thy (n ⫽ 59), and no relationship was found between plasma levels of PAPP-A and those of hemostasis parameters and inflammatory cytokines. Multiple logistic regression analyses using PAPP-A as the dependent variable and age, BMI, and biochemical parameters as independent variables showed no associated factors other than A1C (P ⫽ 0.02) and glycemia (P ⫽ 0.04). CONCLUSIONS — In the present study, PAPP-A levels were significantly lower in diabetic patients compared with those in age- and sex-matched control subjects without clinical macrovascular diseases, and, for the first time, a significant inverse correlation was found between PAPP-A and A1C, independent of other clinical and metabolic factors. The relationship between PAPP-A levels and A1C could reflect the influence of glycemic control on the regulation of PAPP-A expression. A possible hypothesis to consider is that PAPP-A may not be a good marker of vascular risk in chronic diseases 3084

such as diabetes. In fact, PAPP-A would be a modulator of proliferative local action of IGF-1 in atherosclerotic plaques (1– 6). IGF-1 acts as a promoter of repair at damaged tissues (4,5,12), and increased PAPP-A levels may reflect a repaired mechanism against vascular damage (10). In previous articles (13), diabetic patients with hypercholesterolemia showed higher PAPP-A levels than control subjects. We do not have an explanation for this disparity in our results; however, in that previous study, PAPP-A levels were measured in diabetic patients with a wide range of A1C, without a hypercholesterolemic control group. No correlations were observed between PAPP-A and clinical and other biochemical data. In previous studies on this topic, there were discrepancies, and some authors have reported a relationship (2,10,14) between PAPP-A and hsCRP, while others have not (11). The lack of an observed correlation between PAPP-A levels and IL-6 or

TNF-␣ could reflect the complex interaction of multiple cytokines, and it is even possible that their exact role in PAPP-A expression is unknown. We found no previous reports on the relationship between plasma PAPP-A levels and the hemostatic parameters evaluated that were selected to globally identify coagulation or fibrinolysis activation in diabetic patients. The absolute PAPP-A serum concentrations found in our study could not be compared with those reported in other studies (2,10,11,15) owing to the different methods used for PAPP-A measurement (16). Acknowledgments — This study was supported by a grant “Ajut a la recerca en diabetis Gonçal Lloveras i Valle`s” from the Catalan Diabetes Association.

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