Osteopenia has been ascribed to diabetics without residual insulin secretion and high insulin requirement. However, it is not known if this is partially due to disturbances in the IGF system, which is a key regulator of bone cell function.To address this question, we performed a cross-sectional study measuring serum levels of IGF-I, IGF-binding protein-1 (IGFBP-1), IGFBP-3, IGFBP-4 and IGFBP-5 by specific immunoassays in 52 adults with Type 1 (n=27) and Type 2 (n=25) diabetes mellitus and 100 age-and sex-matched healthy blood donors. In the diabetic patients, we further determined serum levels of proinsulin, intact parathyroid hormone (PTH), 25-hydroxyvitamin D 3 , 1,25-dihydroxyvitamin D 3 and several biochemical bone markers, including osteocalcin (OSC), bone alkaline phosphatase (B-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 marker of diabetic nephropathy. Bone mineral density (BMD) of hip and lumbar spine was determined by dual-energy X-ray absorptiometry. Data are presented as means ... Differences between the experimental groups were determined by performing a one-way analysis of variance (ANOVA), followed by Newman-Keuls test. Correlations between variables were assessed using univariate linear regression analysis and partial correlation 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, 2910 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 were 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 correlated 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 (83 2%, Z-score) and lumbar spine (93 2%) than Type 2 diabetics (93 5%, 101 5% respectively), reaching significance in the female subgroups (P<0·05). In Type 1 patients, BMD of hip correlated negatively 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 assessed by partial correlation analysis. Furthermore, biochemical markers indicating bone loss (ICTP) and increased bone turnover (PTH, OSC) correlated positively with IGFBP-1 and IGFBP-4 but negatively with IGF-I, IGFBP-3 and IGFBP-5, while the opposite was observed with bone formation markers (PICP, B-ALP) and vitamin D 3 metabolites. In 20 Type 2 patients in whom immunoreactive proinsulin could be detected, significant 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 showe...

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Patients with primary and secondary hyperparathyroidism showed lower levels of the putative stimulatory IGFBP-5 but higher levels of IGFBP-1, -2, -3, and -6, whereas total IGF-I and IGF-II levels were not or only moderately increased. The marked increase in serum levels of IGFBP-4 appeared to be characteristic for chronic renal failure. IGFBP-5 correlated with biochemical markers and histologic indices of bone formation in renal osteodystrophy patients and was not influenced by renal function. Therefore, IGFBP-5 may gain significance as a serological marker for osteopenia and low bone turnover in long-term dialysis patients.

BACKGROUND: Insulin-like growth factor (IGF) system components are important regulators of bone formation. Alterations of individual IGF system components have been described in osteoporosis (OP) patients; however, no study has addressed changes in free IGF-I and in all six IGF binding proteins (IGFBPs). METHODS: A cross-sectional study was performed in 45 OP patients and 100 healthy matched controls. Serum levels of free and total insulin-like growth factor I (IGF-I), IGFBP-1 through -6, intact parathyroid hormone (PTH), 25-OH-vitamin D(3) (25OHD(3)), 1,25-(OH)(2)-vitamin D(3) (1,25-(OH)(2)D(3)), osteocalcin (OSC), bone alkaline phosphatase (B-ALP), and carboxyterminal propeptide of type-I procollagen (PICP) were measured with specific assays. Bone mineral density (BMD) of the lumbar spine was determined by dual-energy X-ray absorptiometry (DEXA). RESULTS: Compared with age- and sex-matched control subjects, OP patients showed a 73% decrease in free IGF-I, a 29% decrease in total IGF-I, a 10% decrease in IGFBP-3, and a 52% decrease in IGFBP-5 levels; they had higher levels of IGFBP-1 (4.1-fold), IGFBP-2 (1.8-fold), IGFBP-4 (1.3-fold), and IGFBP-6 (2.1-fold). Alterations in IGF system components were most evident in 13 OP patients with vertebral fractures in the past 4 years compared to patients without fractures. In OP patients with fractures, the ratio between IGFBP-4 and IGFBP-5 was increased whereas levels of OSC were decreased. CONCLUSIONS: Our data provide strong indirect evidence for a functional connection between circulating IGF system components and bone metabolism and the susceptibility to fractures in OP patients.

Insulin-like growth factor system components in hyperparathypositive correlations with IGFBP-3 and IGFBP-5 (that is, stimroidism and renal osteodystrophy.ulatory IGF system components). A positive correlation was Background. The insulin-like growth factor (IGF) system observed between IGF-II and IGFBP-6. ESRF patients with plays a key role in regulation of bone formation. In patients mixed uremic bone disease and histologic evidence for osteopewith renal osteodystrophy, an elevation of some IGF binding proteins (IGFBPs) has been described, but there is no study nia revealed significantly (P Ͻ 0.05) higher levels of IGFBP-2 measuring serum levels of both IGF-I and IGF-II as well as and IGFBP-4 but lower IGFBP-5 levels. Histologic parameters IGFBP-1 to -6 in different forms of renal osteodystrophy and of bone formation showed significant positive correlations with hyperparathyroidism.serum levels of IGF-I, IGF-II, and IGFBP-5. In contrast, Methods. In a cross-sectional study, we investigated 319 pa-IGFBP-2 and IGFBP-4 correlated positively with indices of tients with mild (N ϭ 29), moderate (N ϭ 48), preuremic (N ϭ bone loss. Moreover, dialysis patients with low bone turn-37), and end-stage renal failure (ESRF; N ϭ 205). The ESRF over (N ϭ 24) showed significantly (P Ͻ 0.05) lower levels of group was treated by hemodialysis (HD; N ϭ 148), peritoneal IGFBP-5, PTH, B-ALP, and OSC than patients with high bone dialysis (PD; N ϭ 27), or renal transplantation (RTX; N ϭ 30).turnover. As controls without renal failure, we recruited age-matched Conclusion. Patients with primary and secondary hyperparahealthy subjects (N ϭ 87) and patients with primary hyperparathyroidism showed lower levels of the putative stimulatory thyroidism (pHPT; N ϭ 25). Serum levels of total and free IGFBP-5 but higher levels of IGFBP-1, -2, -3, and -6, whereas IGF-I, IGF-II, IGFBP-1 to -6, and biochemical bone markers total IGF-I and IGF-II levels were not or only moderately including intact parathyroid hormone (PTH), bone alkaline increased. The marked increase in serum levels of IGFBP-4 phosphatase (B-ALP), and osteocalcin (OSC) were measured appeared to be characteristic for chronic renal failure. IGFBP-5 by specific immunometric assays. IGF system components and correlated with biochemical markers and histologic indices of bone markers were correlated with clinical and bone histologic bone formation in renal osteodystrophy patients and was not findings. Mean values Ϯ sem are given.influenced by renal function. Therefore, IGFBP-5 may gain Results. With declining renal function a significant increase significance as a serological marker for osteopenia and low was measured for IGFBP-1 (range 7-to 14-fold), IGFBP-2 bone turnover in long-term dialysis patients. (3-to 8-fold), IGFBP-3 (1.5-to 3-fold), IGFBP-4 (3-to 19fold), and IGFBP-6 (8-to 25-fold), whereas IGFBP-5 levels tended to decrease (1.3-to 1.6-fold). In contrast, serum levels of IGF-I, free IGF-I, and IGF-II remained constant in most Bone remodeling is regulated by systemic hormones patien...