Associations between insulin-like growth factor binding protein-2 and insulin sensitivity, metformin, and mortality in persons with T2D

Rikke Hjortebjerg; Maja R Kristiansen; Ivan Brandslund; Dorte Aa Olsen; Jacob V Stidsen; Jens S Nielsen; Jan Frystyk

doi:10.1016/j.diabres.2023.110977

Associations between insulin-like growth factor binding protein-2 and insulin sensitivity, metformin, and mortality in persons with T2D

Diabetes Res Clin Pract. 2023 Nov:205:110977. doi: 10.1016/j.diabres.2023.110977. Epub 2023 Oct 25.

Authors

Rikke Hjortebjerg¹, Maja R Kristiansen², Ivan Brandslund³, Dorte Aa Olsen³, Jacob V Stidsen⁴, Jens S Nielsen⁵, Jan Frystyk⁶

Affiliations

¹ Steno Diabetes Center Odense, Odense University Hospital, Odense, Denmark; Department of Clinical Research, University of Southern Denmark, Denmark; Endocrine Research Unit, Molecular Endocrinology Laboratory (KMEB), Department of Endocrinology, Odense University Hospital, Denmark. Electronic address: rhjortebjerg@health.sdu.dk.
² Steno Diabetes Center Odense, Odense University Hospital, Odense, Denmark; Danish Centre for Strategic Research in Type 2 Diabetes (DD2), Odense, Denmark.
³ Department of Biochemistry and Immunology, University Hospital of Southern Denmark, Vejle, Denmark.
⁴ Steno Diabetes Center Odense, Odense University Hospital, Odense, Denmark; Endocrine Research Unit, Molecular Endocrinology Laboratory (KMEB), Department of Endocrinology, Odense University Hospital, Denmark.
⁵ Steno Diabetes Center Odense, Odense University Hospital, Odense, Denmark; Department of Clinical Research, University of Southern Denmark, Denmark; Danish Centre for Strategic Research in Type 2 Diabetes (DD2), Odense, Denmark.
⁶ Department of Clinical Research, University of Southern Denmark, Denmark; Endocrine Research Unit, Molecular Endocrinology Laboratory (KMEB), Department of Endocrinology, Odense University Hospital, Denmark.

PMID: 37890435
DOI: 10.1016/j.diabres.2023.110977

Abstract

Aims: Serum insulin-like growth factor binding protein-2 (IGFBP-2) is low in persons with type 2 diabetes mellitus (T2D) and possibly regulated by metformin. Counter-intuitively, high IGFBP-2 associates with mortality. We investigated the association between IGFBP-2, metformin-treatment, and indices of insulin sensitivity, and assessed IGFBP-2 in relation to prior comorbidity and mortality during five-year follow-up.

Methods: The study included 859 treatment-naive and 558 metformin-treated persons enrolled in the Danish Centre for Strategic Research in T2D and followed for 4.9 (3.9-5.9) years through national health registries. All proteins were determined in serum collected at enrollment.

Results: Following adjustment for age, metformin-treated and treatment-naive persons has similar IGFBP-2 levels. Low IGFBP-2 level was associated with increased BMI, fasting glucose, and C-peptide. IGFBP-2 was higher in the 437 persons who had comorbidities at enrollment than in those with T2D only (343 (213;528) vs. 242 (169;378) ng/mL). During follow-up, 87 persons died, and IGFBP-2 predicted mortality with an unadjusted HR (95% CI) per doubling in IGFBP-2 concentration of 2.62 (2.04;3.37) and a HR of 2.21 (1.61;3.01) following full adjustment.

Conclusions: In T2D, high IGFBP-2 associates with low glucose and insulin secretion, is unaffected by metformin treatment, and associates with risk of prior comorbidity and mortality.

Keywords: Comorbidity, insulin-like growth factor binding protein-2; Insulin sensitivity; Metformin; Mortality; Type 2 diabetes mellitus.

MeSH terms

Diabetes Mellitus, Type 2* / drug therapy
Glucose
Humans
Insulin
Insulin Resistance*
Insulin-Like Growth Factor Binding Protein 2
Insulin-Like Growth Factor I / metabolism
Metformin* / therapeutic use

Substances

Metformin
Insulin-Like Growth Factor Binding Protein 2
Glucose
Insulin
Insulin-Like Growth Factor I