SERUM LEVELS OF INSULIN-LIKE-GROWTH-FACTOR SYSTEM COMPONENTS AND RELATIONSHIP TO BONE METABOLISM IN TYPE-1 AND TYPE-2 DIABETES-MELLITUS PATIENTS

Osteopenia has been ascribed to diabetics without residual insulin sec retion and high insulin requirement. However, it is not known if this is partially due to disturbances in the IGF system, which is a key reg ulator of bone cell function. To address this question, we performed a cross-sectional study measuring serum levels of IGF-I, IGF-binding pr otein-1 (IGFBP-1), IGFBP-3, IGFBP-4 and IGFBP-5 by specific immunoassa ys in 52 adults with Type I (n=27) and Type 2 (n=25) diabetes mellitus and 100 age- and sex-matched healthy blood donors. In the diabetic pa tients, we further determined serum levels of proinsulin, intact parat hyroid hormone (PTH), 25-hydroxyvitamin D-3, 1,25-dihydroxyvitamin D-3 and several biochemical bone markers, including osteocalcin (OSC), bo ne alkaline phosphatase CB-ALP), carboxy-terminal propeptide of type I procollagen (PICP), and type I collagen cross-linked carboxy-terminal telopeptide (ICTP). Urinary albumin excretion was ascertained as a ma rker of diabetic nephropathy. Bone mineral density (BMD) of hip and lu mbar spine was determined by dual-energy X-ray absorptiometry. Data ar e presented as means +/- S.E.M. Differences between the experimental g roups were determined by performing a one-way analysis of variance (AN OVA), followed by Newman-Keuls test. Correlations between variables we re assessed using univariate linear regression analysis and partial co rrelation analysis. Type 1 diabetics showed significantly lower IGF-I (119 +/- 8 ng/ml) and IGFBP-3 (2590 +/- 104 ng/ml) but higher IGFBP-1 levels (38 +/- 10 ng/ml) compared with Type 2 patients (170 +/- 13, 29 10 +/- 118, 11 +/- 3 respectively; P<0.05) or healthy controls (169 +/ - 5, 4620 +/- 192, 3.5 +/- 0.4 respectively; P<0.01). IGFBP-5 levels w ere markedly lower in both diabetic groups (Type 1, 228 +/- 9; Type 2, 242 +/- 11 ng/ml) than in controls (460 +/- 7 ng/ml, P<0.01), whereas IGFBP-4 levels were similar in diabetics and controls. IGF-I correlat ed positively with IGFBP-3 and IGFBP-5 and negatively with IGFBP-1 and IGFBP-4 in all subjects. Type 1 patients showed a lower BMD of hip (8 3 +/- 2%, Z-score) and lumbar spine (93 +/- 2%) than Type 2 diabetics (93 +/- 5%, 101 +/- 5% respectively), reaching significance in the fem ale subgroups (P<0.05). In Type 1 patients, BMD of hip correlated nega tively with IGFBP-1 (r = - 0.34, P<0.05) and IGFBP-4 (r= - 0.3, P<0.05 ) but positively with IGFBP-5 (r=0.37, P<0.05), which was independent of age, diabetes duration, height, weight and body mass index, as asse ssed by partial correlation analysis. Furthermore, biochemical markers indicating bone loss (ICTP) and increased bone turnover (PTH, OSC) co rrelated positively with IGFBP-1 and IGFBP-4 but negatively with IGF-I , IGFBP-3 and IGFBP-5, while the opposite was observed with bone forma tion markers (PICP, B-ALP) and vitamin D-3 metabolites. In 20 Type 2 p atients in whom immunoreactive proinsulin could be detected, significa nt positive correlations were found between proinsulin and BMD of hip (r=0.63, P<0.005), IGF-I (r=0.59, P<0.01) as well as IGFBP-3 (r=0.49, P<0.05). Type 1 and Type 2 patients with macroalbuminuria showed a low er BMD of hip, lower IGFBP-5 but higher IGFBP-4 levels, suggesting tha t diabetic nephropathy may contribute to bone loss by a disturbed IGF system. In conclusion, the findings of this study support the hypothes is that the imbalance between individual IGF system components and the lack of endogenous proinsulin may contribute to the lower BMD in Type 1 diabetics.