title: IGFBP-4 Fragments as Markers of Cardiovascular Mortality in Type 1 Diabetes Patients With and Without Nephropathy.
abstract: BACKGROUND
  Type 1 diabetes (T1D) is characterized by an increased risk of macrovascular complications. Pregnancy-associated plasma protein-A (PAPP-A) generated N- and C-terminal fragments of IGF binding protein-4 (NT-IGFBP-4 and CT-IGFBP-4) have been suggested as cardiac biomarkers.
  
  
  OBJECTIVE
  The objective of the study was to investigate the prognostic value of IGFBP-4 fragments in a cohort of T1D patients.
  
  
  METHODS
  We prospectively followed up 178 T1D patients with diabetic nephropathy and 152 T1D patients with normoalbuminuria for 12.6 (range 0.2-12.9) years.
  
  
  METHODS
  Levels of IGF-1, IGF-2, IGFBP-1-4, NT- and CT-IGFBP-4, and PAPP-A at baseline.
  
  
  RESULTS
  During follow-up, 15 patients with normoalbuminuria and 71 patients with nephropathy died. Of these deaths, 8 and 45 were due to fatal cardiovascular events, respectively. Using receiver-operating characteristic curve analyses, patients were divided into subgroups using cutoff values of 261 μg/L NT-IGFBP-4, 81 μg/L CT-IGFBP-4, or 10 mIU/L PAPP-A. All-cause mortality was significantly higher in patients with NT-IGFBP-4 levels (55% vs 16%, P < .001) and CT-IGFBP-4 levels (44% vs 15%, P < .001) above vs below cutoffs. Similarly, cardiovascular mortality was elevated in patients with high NT-IGFBP-4 levels (40% vs 7.8%, P < .001) and high CT-IGFBP-4 levels (30% vs 7.4%, P < .001). After adjustments for nephropathy and traditional cardiovascular risk factors, high NT- and CT-IGFBP-4 levels remained prognostic of cardiovascular mortality with hazard ratios [95% confidence interval (CI)] of 5.81 (95% CI 2.62-12.86) (P < .001) and 2.58 (95% CI 1.10-6.10) (P = .030), respectively. After adjustments, PAPP-A was not associated with overall or cardiovascular death. All IGF protein levels were higher in patients with diabetic nephropathy (P < .001), but no variables associated with mortality.
  
  
  CONCLUSIONS
  High IGFBP-4 fragment levels were associated with increased all-cause and cardiovascular mortality rates in T1D patients with and without diabetic nephropathy.
authors.affiliation: Medical Research Laboratory (R.H., M.B., J.F.), Department of Clinical Medicine, Faculty of Health, and Faculty of Health (L.T., H.-H.P., P.R.), Aarhus University, and Departments of Heart Diseases (A.J.) and Endocrinology and Internal Medicine (J.F.), Aarhus University Hospital, DK-8000 Aarhus, Denmark; The Danish Diabetes Academy (R.H.), DK-5000 Odense, Denmark; Steno Diabetes Center (L.T., A.J., P.R.), Gentofte, DK-2820 Copenhagen, Denmark; Nordsjællands Hospital (L.T.), DK-3400 Hillerød, Denmark; Department of Medical Endocrinology (H.-H.P.), Rigshospitalet, University of Copenhagen, DK-2100 Copenhagen, Denmark; and The Novo Nordisk Foundation Center for Basic Metabolic Research (P.R.), University of Copenhagen, DK-2300 Copenhagen, Denmark.
authors.forename: Rikke
authors.initials: R
authors.lastname: Hjortebjerg
authors.affiliation: Medical Research Laboratory (R.H., M.B., J.F.), Department of Clinical Medicine, Faculty of Health, and Faculty of Health (L.T., H.-H.P., P.R.), Aarhus University, and Departments of Heart Diseases (A.J.) and Endocrinology and Internal Medicine (J.F.), Aarhus University Hospital, DK-8000 Aarhus, Denmark; The Danish Diabetes Academy (R.H.), DK-5000 Odense, Denmark; Steno Diabetes Center (L.T., A.J., P.R.), Gentofte, DK-2820 Copenhagen, Denmark; Nordsjællands Hospital (L.T.), DK-3400 Hillerød, Denmark; Department of Medical Endocrinology (H.-H.P.), Rigshospitalet, University of Copenhagen, DK-2100 Copenhagen, Denmark; and The Novo Nordisk Foundation Center for Basic Metabolic Research (P.R.), University of Copenhagen, DK-2300 Copenhagen, Denmark.
authors.forename: Lise
authors.initials: L
authors.lastname: Tarnow
authors.affiliation: Medical Research Laboratory (R.H., M.B., J.F.), Department of Clinical Medicine, Faculty of Health, and Faculty of Health (L.T., H.-H.P., P.R.), Aarhus University, and Departments of Heart Diseases (A.J.) and Endocrinology and Internal Medicine (J.F.), Aarhus University Hospital, DK-8000 Aarhus, Denmark; The Danish Diabetes Academy (R.H.), DK-5000 Odense, Denmark; Steno Diabetes Center (L.T., A.J., P.R.), Gentofte, DK-2820 Copenhagen, Denmark; Nordsjællands Hospital (L.T.), DK-3400 Hillerød, Denmark; Department of Medical Endocrinology (H.-H.P.), Rigshospitalet, University of Copenhagen, DK-2100 Copenhagen, Denmark; and The Novo Nordisk Foundation Center for Basic Metabolic Research (P.R.), University of Copenhagen, DK-2300 Copenhagen, Denmark.
authors.forename: Anders
authors.initials: A
authors.lastname: Jorsal
authors.affiliation: Medical Research Laboratory (R.H., M.B., J.F.), Department of Clinical Medicine, Faculty of Health, and Faculty of Health (L.T., H.-H.P., P.R.), Aarhus University, and Departments of Heart Diseases (A.J.) and Endocrinology and Internal Medicine (J.F.), Aarhus University Hospital, DK-8000 Aarhus, Denmark; The Danish Diabetes Academy (R.H.), DK-5000 Odense, Denmark; Steno Diabetes Center (L.T., A.J., P.R.), Gentofte, DK-2820 Copenhagen, Denmark; Nordsjællands Hospital (L.T.), DK-3400 Hillerød, Denmark; Department of Medical Endocrinology (H.-H.P.), Rigshospitalet, University of Copenhagen, DK-2100 Copenhagen, Denmark; and The Novo Nordisk Foundation Center for Basic Metabolic Research (P.R.), University of Copenhagen, DK-2300 Copenhagen, Denmark.
authors.forename: Hans-Henrik
authors.initials: HH
authors.lastname: Parving
authors.affiliation: Medical Research Laboratory (R.H., M.B., J.F.), Department of Clinical Medicine, Faculty of Health, and Faculty of Health (L.T., H.-H.P., P.R.), Aarhus University, and Departments of Heart Diseases (A.J.) and Endocrinology and Internal Medicine (J.F.), Aarhus University Hospital, DK-8000 Aarhus, Denmark; The Danish Diabetes Academy (R.H.), DK-5000 Odense, Denmark; Steno Diabetes Center (L.T., A.J., P.R.), Gentofte, DK-2820 Copenhagen, Denmark; Nordsjællands Hospital (L.T.), DK-3400 Hillerød, Denmark; Department of Medical Endocrinology (H.-H.P.), Rigshospitalet, University of Copenhagen, DK-2100 Copenhagen, Denmark; and The Novo Nordisk Foundation Center for Basic Metabolic Research (P.R.), University of Copenhagen, DK-2300 Copenhagen, Denmark.
authors.forename: Peter
authors.initials: P
authors.lastname: Rossing
authors.affiliation: Medical Research Laboratory (R.H., M.B., J.F.), Department of Clinical Medicine, Faculty of Health, and Faculty of Health (L.T., H.-H.P., P.R.), Aarhus University, and Departments of Heart Diseases (A.J.) and Endocrinology and Internal Medicine (J.F.), Aarhus University Hospital, DK-8000 Aarhus, Denmark; The Danish Diabetes Academy (R.H.), DK-5000 Odense, Denmark; Steno Diabetes Center (L.T., A.J., P.R.), Gentofte, DK-2820 Copenhagen, Denmark; Nordsjællands Hospital (L.T.), DK-3400 Hillerød, Denmark; Department of Medical Endocrinology (H.-H.P.), Rigshospitalet, University of Copenhagen, DK-2100 Copenhagen, Denmark; and The Novo Nordisk Foundation Center for Basic Metabolic Research (P.R.), University of Copenhagen, DK-2300 Copenhagen, Denmark.
authors.forename: Mette
authors.initials: M
authors.lastname: Bjerre
authors.affiliation: Medical Research Laboratory (R.H., M.B., J.F.), Department of Clinical Medicine, Faculty of Health, and Faculty of Health (L.T., H.-H.P., P.R.), Aarhus University, and Departments of Heart Diseases (A.J.) and Endocrinology and Internal Medicine (J.F.), Aarhus University Hospital, DK-8000 Aarhus, Denmark; The Danish Diabetes Academy (R.H.), DK-5000 Odense, Denmark; Steno Diabetes Center (L.T., A.J., P.R.), Gentofte, DK-2820 Copenhagen, Denmark; Nordsjællands Hospital (L.T.), DK-3400 Hillerød, Denmark; Department of Medical Endocrinology (H.-H.P.), Rigshospitalet, University of Copenhagen, DK-2100 Copenhagen, Denmark; and The Novo Nordisk Foundation Center for Basic Metabolic Research (P.R.), University of Copenhagen, DK-2300 Copenhagen, Denmark.
authors.forename: Jan
authors.initials: J
authors.lastname: Frystyk
mesh_terms: D000328:Adult; D015415:Biomarkers / Q000097:blood*; D002318:Cardiovascular Diseases / Q000097:blood / Q000175:diagnosis / Q000401:mortality*; D002423:Cause of Death; D003922:Diabetes Mellitus, Type 1 / Q000097:blood / Q000150:complications / Q000175:diagnosis / Q000401:mortality*; D003928:Diabetic Nephropathies / Q000097:blood / Q000175:diagnosis / Q000401:mortality*; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D018974:Insulin-Like Growth Factor Binding Protein 4 / Q000097:blood* / Q000737:chemistry; D008297:Male; D008875:Middle Aged; D010446:Peptide Fragments / Q000097:blood*; D011247:Pregnancy; D011379:Prognosis; D012307:Risk Factors
chemical_list: D015415:Biomarkers; D018974:Insulin-Like Growth Factor Binding Protein 4; D010446:Peptide Fragments