IGFBP-4 Fragments as Markers of Cardiovascular Mortality in Type 1 Diabetes Patients With and Without Nephropathy.

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.
The objective of the study was to investigate the prognostic value of IGFBP-4 fragments in a cohort of T1D patients.
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.
Levels of IGF-1, IGF-2, IGFBP-1-4, NT- and CT-IGFBP-4, and PAPP-A at baseline.
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.
High IGFBP-4 fragment levels were associated with increased all-cause and cardiovascular mortality rates in T1D patients with and without diabetic nephropathy.
AuthorsRikke Hjortebjerg, Lise Tarnow, Anders Jorsal, Hans-Henrik Parving, Peter Rossing, Mette Bjerre, Jan Frystyk
JournalThe Journal of clinical endocrinology and metabolism (J Clin Endocrinol Metab) Vol. 100 Issue 8 Pg. 3032-40 (Aug 2015) ISSN: 1945-7197 [Electronic] United States
PMID26046968 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References
  • Biomarkers
  • Insulin-Like Growth Factor Binding Protein 4
  • Peptide Fragments
  • Adult
  • Biomarkers (blood)
  • Cardiovascular Diseases (blood, diagnosis, mortality)
  • Cause of Death
  • Diabetes Mellitus, Type 1 (blood, complications, diagnosis, mortality)
  • Diabetic Nephropathies (blood, diagnosis, mortality)
  • Female
  • Follow-Up Studies
  • Humans
  • Insulin-Like Growth Factor Binding Protein 4 (blood, chemistry)
  • Male
  • Middle Aged
  • Peptide Fragments (blood)
  • Pregnancy
  • Prognosis
  • Risk Factors

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