Osteopontin Is a Strong Predictor of Incipient Diabetic Nephropathy, Cardiovascular Disease, and All-Cause Mortality in Patients With Type 1 Diabetes

Daniel Gordin; Carol Forsblom; Nicolae M. Panduru; Merlin C. Thomas; Mette Bjerre; Aino Soro-Paavonen; Nina Tolonen; Niina Sandholm; Allan Flyvbjerg; Valma Harjutsalo; Per-Henrik Groop

Disclosures

Diabetes Care. 2014;37(9):2593-2600. 

In This Article

Abstract and Introduction

Abstract

Objective Osteopontin (OPN) is a multifunctional protein suggested to be a player in the arterial disease of patients with type 2 diabetes. However, its role for complications in patients with type 1 diabetes (T1D) is unknown. We therefore investigated the associations between OPN and diabetic vascular complications and all-cause mortality in patients with T1D.

Research Design and Methods Serum OPN was measured in 2,145 adults with T1D without end-stage renal disease (ESRD; dialysis or transplantation) as part of the Finnish Diabetic Nephropathy (FinnDiane) Study. Data on renal status, cardiovascular disease (CVD), and all-cause mortality during follow-up were verified from medical files, hospital discharge registries, and the Finnish National Death Registry, respectively. The median follow-up time was 10.5 (interquartile range 8.9–11.8) years.

Results Serum OPN was higher at baseline in patients who developed incident microalbuminuria (16.0 ± 0.9 vs. 14.1 ± 0.2 μg/L; P = 0.04), progressed to ESRD (28.3 ± 1.7 vs. 15.4 ± 0.2 μg/L; P < 0.001), suffered an incident CVD event (20.2 ± 1.2 vs. 15.5 ± 0.2 μg/L; P < 0.001), or died (23.3 ± 1.4 vs. 15.8 ± 0.2 μg/L; P < 0.001) during follow-up. In multivariate Cox regression analysis, OPN was independently associated with the development of incident microalbuminuria, an incident CVD event, and death, after adjustments for associated risk factors. Even after calculating reclassification indexes, OPN was predictive of CVD and all-cause mortality beyond the Framingham risk score covariates and hs-CRP.

Conclusions Serum OPN is a strong predictor of incipient diabetic nephropathy, a first-ever CVD event, and all-cause mortality in patients with T1D. Serum OPN may be of clinical significance for the risk prediction of CVD events in patients with T1D.

Introduction

Osteopontin (OPN) is a multifunctional protein expressed by several different cell types, although the bone is known to be a major source.[1] The exact excretion pathway of OPN from the body is not known. OPN is involved in a number of physiological and pathological conditions, including cancer and progression of metastases,[2] urinary stones,[3] wound healing,[4] chronic inflammatory and autoimmune diseases,[5] obesity-related chronic inflammation, and insulin resistance.[6] However, OPN was originally found in bone and shown to regulate the formation and calcification of bone tissue.[7] Notably, OPN has also been linked to vascular remodelling and calcification, especially in diabetic arteries,[8] and has been shown to associate with diabetic retinopathy[9] and nephropathy[10] in patients with type 2 diabetes (T2D), as well as cardiovascular disease (CVD) events in nondiabetic subjects with a history of coronary artery disease (CAD).[11] However, its role for late complications in patients with type 1 diabetes (T1D) is not known. Furthermore, the risk factor profile for vascular complications differs in T1D from that in T2D. The increased risk for CVD events in T2D is linked to the presence of hypertension, dyslipidemia, overweight, and insulin resistance, whereas the primary determinant of health in T1D is renal disease.[12,13]

We therefore explored the association between serum OPN and diabetic vascular complications as well as all-cause mortality in a large well-characterized cohort of patients with T1D.

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