Serum levels of insulin-like growth factor system components and relationship to bone metabolism in Type 1 and Type 2 diabetes mellitus patients

Abstract

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...

Microarray profiling of skeletal muscle tissues from equally obese, non-diabetic insulin-sensitive and insulin-resistant Pima Indians

“…The serum protein concentration of IGFBP5 was lower in diabetic patients compared to the control subjects [41], and diabetic rat kidney contains reduced IGFBP5 mRNA concentrations [42]. Nevertheless, the expression of IGFBP5 in skeletal muscle is not altered acutely by nutrients and insulin [43].…”

Lack of relationship between glycemic control and bone mineral density in type 2 diabetes mellitus

“…Theoretically, several mechanisms may be suggested to be responsible for low bone mass in DM, such as insulinopenia (14,15), microangiopathy (16,17) and increased interleukin elevation (18). In turn, the lack of metabolic control may potentially affect also the maintenance of bone mass, interfering not only with the equilibrium of mineral metabolism (19,20), but also with bone remodeling activity (21,22).…”

“…Thus, it is possible that the association of DM with osteopenia represents one more aspect of the heterogeneity of this disorder. Type 2 DM is associated with obesity, hyperandrogenism, elevation of estrogen levels, normal IGFI, and frequently hyperinsulinemia, (15,31,32), which are factors that protect against the loss of bone mass. In contrast, type 1 DM is associated with insulinopenia, weight loss, low IGFI levels (15), and frequently with amenorrhea and hypoestrogenism, which are associated with osteopenia.…”

“…Type 2 DM is associated with obesity, hyperandrogenism, elevation of estrogen levels, normal IGFI, and frequently hyperinsulinemia, (15,31,32), which are factors that protect against the loss of bone mass. In contrast, type 1 DM is associated with insulinopenia, weight loss, low IGFI levels (15), and frequently with amenorrhea and hypoestrogenism, which are associated with osteopenia. The present data indicate that hyperglycemia does not seem to be a mechanism involved in the induction of osteopenia, since the lack of metabolic control does not cause significant changes in the biochemical parameters of mineral metabolism control, i.e., PTH and 25-OH-D, or in the parameters that reflect bone remodeling activity.…”

Diabetes and premature menopause: is their co-existence detrimental to the skeleton?

“…In the past, various studies have illustrated a positive effect of type 2 diabetes on bone mass (16)(17)(18) and in an attempt to explain this finding, investigators proposed specific pathophysiological mechanisms such as obesity, hyperinsulinaemia (16), or increased concentrations of growth factors (insulin-like growth factors (IGFs)) (17). Up to now, studies that have addressed the influence of type 2 diabetes on the bone metabolism of postmenopausal women have mainly dealt with normal menopause.…”