IGF-binding protein 1 and abdominal obesity in the development of type 2 diabetes in women

Abstract

Objective: Low levels of IGF-binding protein 1 (IGFBP1) are associated with metabolic syndrome and predict diabetes development in men. The aim of this study was to determine the levels of IGFBP1 in women who later develop diabetes, in relation to abdominal obesity, and to compare these levels with those of men.

Methods: IGFBP1 levels were determined at baseline and after 8 years in a case-control, prospective study of Swedish women aged 35-56 years. Individuals with normal oral glucose tolerance test (OGTT) who developed abnormal glucose regulation (n=240) were pair matched to controls for age and family history of diabetes and also compared to men of the same age (n=355).

Results: Low fasting IGFBP1 and increased waist measurement predicted development of diabetes in women (n=60; odds ratio (OR) 70, 95% confidence interval (CI) 8-661, lowest tertile and OR 27, 95% CI 5-141, highest tertile). In women developing diabetes, baseline IGFBP1 levels were lower than expected for fasting insulin values, were associated with impaired suppression after OGTT and increased during 8 years despite an increase in fasting insulin. All individuals in the highest tertile for waist and with <or=40% suppression of IGFBP1 developed diabetes within 8 years. Circulating IGFBP1 concentrations were higher in women compared to men. Women and men who developed diabetes had a similar degree of abdominal obesity, corrected for height.

Conclusions: We conclude that low IGFBP1 and elevated waist measurement predict diabetes development and that IGFBP1 production is suppressed by a novel factor(s) in women developing diabetes. Increasing levels of IGFBP1 during the emergence of diabetes in men and women suggest the emergence of hepatic insulin resistance.

Figure 1

Study design: selection and follow-up of women in the Stockholm Diabetes Prevention Programme. The groups from which the present study population was derived were categorized according to 1999 WHO criteria and are shown in bold type. FHD+, family history of diabetes; FHD−, no family history of diabetes; GDM, history of gestational diabetes; T2DM, type 2 diabetes mellitus. *Exclusion criteria: already known diabetes (1.5%), unclear FHD (28.5%), insufficient FHD according to inclusion criteria (9.9%), foreign origin (7.6%), moved or deceased (2.0%). **Subjects aged 35–44 years born in the last third of each month were excluded for financial reasons.

Figure 2

Relationship between IGFBP1 and insulin concentrations in women developing type 2 diabetes at baseline (a and c) and at 8-year follow-up (b and d). The relationship between fasting values is shown in (a) and (b) (n=60), while the fasting and 2-h response (means and 95% CI) to a 75 g OGTT are shown for the 37 individuals undergoing this test both at baseline (c) and at follow-up (d). The individuals developing diabetes are represented by the solid circles and unbroken regression lines, and are compared to their matched controls, which are represented by the open circles and broken regression lines. Regression lines and correlation coefficients: (a) controls: ²log(IGFBP1)=9.394−(0.661ײlog(insulin)), r=−0.55, P<0.001; diabetes: ²log(IGFBP1)=8.065−(0.531ײlog(insulin)), r=−0.40, P=0.002; (b) controls: ²log(IGFBP1)=10.020−(0.738ײlog(insulin)), r=−0.53, P<0.001; diabetes: ²log(IGFBP1)=9.766−(0.677ײlog(insulin)), r=−0.64, P<0.001.

Figure 3

Relationship between the suppression of IGFBP1 by oral glucose and the fasting (f)-IGFBP1 levels and Wa²HtR. The suppression of IGFBP1 at 2 h at baseline, expressed as a percentage of the fasting values, is related to the fasting (f)-IGFBP1 in women at baseline, 8 years before the development of diabetes (a), to the increase in waist measurement (Wa²HtR) over 8 years (b) and to the baseline Wa²HtR (c). The individuals developing diabetes (n=60) are represented by the solid circles and unbroken regression lines, and are compared to their matched controls, which are represented by the open circles. The vertical line represents the cut-off value of the highest tertile for Wa²HtR (c). Correlation coefficients: (a) controls: r=−0.30, P=0.018; diabetes: r=−0.71, P<0.001; (b) controls: r=−0.23, P=0.074; diabetes: r=0.47, P<0.001; (c) controls: r=0.05, P=0.702; diabetes: r=0.34, P=0.008.

Figure 4

ORs (95% CIs) of variables for the development of IGT (a), IFG or IFG+IGT (b) and type 2 diabetes (c) in women. The lowest tertile was used as the reference in the calculation. Note that the inverse of IGFBP1 was used. f, fasting.

Figure 5

Relationship between the change in fasting IGFBP1 and the change in fasting insulin (a) or the change in IGF1 (b) in women developing diabetes at 8-year follow-up. The individuals developing diabetes (n=60) are represented by the solid circles and unbroken regression lines, and are compared with their matched controls, which are represented by the open circles and broken regression lines. Correlation coefficients: (a) controls: r=−0.54, P<0.001; diabetes: r=−0.16, P=0.212; (b) controls: r=−0.20, P=0.117; diabetes: r=−0.52, P<0.001.