The IGF system in patients with type 2 diabetes: associations with markers of cardiovascular target organ damage.
OBJECTIVE
Perturbations in the insulin-like growth factor (IGF) system may contribute to the accelerated cardiovascular disease (CVD) that occurs in patients with type 2 diabetes (T2D). However, it remains unknown whether the IGF system is also involved in the development of early, subclinical CVD. We characterised the IGF system in T2D patients and matched controls and examined the associations with markers of subclinical target organ damage.


METHODS
The study included 99 patients with recently diagnosed T2D and 99 age- and sex-matched controls. IGF-1 and IGFBP-1 to -4 were measured by immunoassays, as were pregnancy-associated plasma protein-A (PAPP-A) and the PAPP-A-generated N-terminal (NT) and C-terminal (CT) IGFBP-4 fragments, which are novel CVD risk markers. Arterial stiffness was evaluated by carotid-femoral pulse wave velocity (PWV). Cerebral white matter lesions (WMLs) and carotid artery remodelling were determined by MRI.


RESULTS
After multivariate adjustments, patients with T2D had lower concentrations of IGFBP-2, IGFBP-4, NT- and CT-IGFBP-4, when compared with controls. IGFBP-2 was inversely correlated to PWV in all subjects in multivariate analysis (P< 0.05), and IGFBP-3 was inversely associated with severity of WMLs (P< 0.05). The NT-IGFBP-4 fragment was associated with the degree of carotid artery remodelling among all subjects (regression coefficient (95% CI): 2.95 (0.70, 5.16),P= 0.011). Levels of NT- and CT-IGFBP-4 were reduced in T2D patients receiving metformin compared to those in controls and patients not receiving metformin.


CONCLUSIONS
Even in recently diagnosed and well-controlled T2D patients, IGF protein levels are altered and associated with CVD risk factors.
Department of Clinical MedicineMedical Research Laboratory, Faculty of Health, Aarhus University, Aarhus, Denmark.|The Danish Diabetes AcademyOdense, Denmark.
Rikke
R
Hjortebjerg
The Danish Diabetes AcademyOdense, Denmark.|Department of Endocrinology and Internal MedicineAarhus University Hospital, Aarhus, Denmark.
Esben
E
Laugesen
Department of Endocrinology and Internal MedicineAarhus University Hospital, Aarhus, Denmark.
Pernille
P
Høyem
Department of Molecular Biology and GeneticsFaculty of Science & Technology, Aarhus University, Aarhus, Denmark.
Claus
C
Oxvig
Department of RadiologySection of Magnetic Resonance Imaging.
Brian
B
Stausbøl-Grøn
Department of Endocrinology and Internal MedicineAarhus University Hospital, Aarhus, Denmark.
Søren T
ST
Knudsen
Department of RadiologySection of Magnetic Resonance Imaging.|Department of CardiologyAarhus University Hospital, Aarhus, Denmark.
Won Y
WY
Kim
Department of Endocrinology and Internal MedicineAarhus University Hospital, Aarhus, Denmark.
Per L
PL
Poulsen
Department of Endocrinology and Internal MedicineAarhus University Hospital, Aarhus, Denmark.
Troels K
TK
Hansen
Department of Clinical MedicineMedical Research Laboratory, Faculty of Health, Aarhus University, Aarhus, Denmark.
Mette
M
Bjerre
Department of Clinical MedicineMedical Research Laboratory, Faculty of Health, Aarhus University, Aarhus, Denmark.|Department of Endocrinology and Internal MedicineAarhus University Hospital, Aarhus, Denmark.
Jan
J
Frystyk
D000368:Aged; D015415:Biomarkers / Q000097:blood; D002318:Cardiovascular Diseases / Q000097:blood* / Q000175:diagnosis* / Q000453:epidemiology; D003924:Diabetes Mellitus, Type 2 / Q000097:blood* / Q000175:diagnosis* / Q000453:epidemiology; D005260:Female; D006801:Humans; D018970:Insulin-Like Growth Factor Binding Protein 1 / Q000097:blood; D018971:Insulin-Like Growth Factor Binding Protein 2 / Q000097:blood*; D018972:Insulin-Like Growth Factor Binding Protein 3 / Q000097:blood; D018974:Insulin-Like Growth Factor Binding Protein 4 / Q000097:blood*; D007334:Insulin-Like Growth Factor I / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D011247:Pregnancy
D015415:Biomarkers; C032231:IGFBP1 protein, human; C515497:IGFBP3 protein, human; D018970:Insulin-Like Growth Factor Binding Protein 1; D018971:Insulin-Like Growth Factor Binding Protein 2; D018972:Insulin-Like Growth Factor Binding Protein 3; D018974:Insulin-Like Growth Factor Binding Protein 4; D007334:Insulin-Like Growth Factor I