The effects of recombinant human insulin-like growth factor I on growth hormone secretion in adolescents with insulin dependent diabetes mellitus

OBJECTIVE It has been proposed that low IGF-I levels and reduced IGF-I bioactivity may lead to elevated GH levels in adolescents with insulin dependent diabetes (IDDM). We have therefore studied the effects of human recombinant insulin-like growth factor I (rhIGF-I) administration on GH levels and GH secretion in adolescents with IDDM. PATIENTS Nine late pubertal adolescents (four male and five female) with IDDM. DESIGN A double-blind placebo controlled study of rhIGF-I administered subcutaneously in a dose of 40 μg/kg body weight at 1800 h. MEASUREMENTS IGF-I and GH concentrations were measured at regular intervals throughout the study. Twenty-two hour GH secretory rates were calculated by deconvolution analysis. Overnight GH profiles were analysed by distribution analysis, and Fourier transformations were performed on both overnight GH concentrations and GH secretory rates. RESULTS Mean IGF-I levels over the 22-hour study period were significantly elevated following rhIGF-I administration (350 ± 26 vs 205 ± 21 μg/l (mean ± SEM), P<0 001). Mean 22-hour GH levels were reduced following rhIGF-I administration (19.4 ± 4.0 compared with 33.6 ± 5.8 mU/l; P= 001). Distribution analysis demonstrated that the reduction in GH levels was due to changes in the proportion of values at both high and low concentrations. Deconvolution analysis also revealed a significant overall reduction in GH secretory rate following IGF-I administration (1.81 ± 0.30 vs 2.98 ± 0.47 mU/min, P= 0.01) which was still apparent during the final 5.5 hours of the study period (1.51 ± 0.30 vs 2.76 ± 0.61 mU/min, P= 002). The dominant periodicity of GH secretory episodes as determined by Fourier transformation was between 120 and 180 minutes after both IGF-I and placebo. CONCLUSIONS In late pubertal adolescents with IDDM the rise in IGF-I levels following rhIGF-l administration in a subcutaneous dose of 40 μg/kg body weight leads to a significant reduction in GH levels and GH secretory rate. The reduction in GH secretion is due to changes in pulse amplitude rather than frequency. A reduction in GH secretion was apparent at the beginning and also towards the end of the 22-hour study period.     

The 'dawn phenomenon' in adolescents with insulin dependent diabetes mellitus: possible contribution of insulin-like growth factor binding protein-1

OBJECTIVE Insulin resistance increases during adolescence, and is exaggerated in patients with insulin dependent diabetes mellitus (IDDM). A relative deficiency of insulin-like growth factor-I (IGF-I) may contribute to this increased insulin requirement. Two mechanisms have been proposed: (a) increased GH secretion, caused by failure of IGF feedback control, leading to increased insulin resistance and (b) lack of Insulin-like action of the IGFs which is reinforced by high plasma levels of IGFBP-1, an inhibitor of IGF action. The contribution of these two mechanisms to the ‘dawn phenomenon’ is assessed. DESIGN The two possible mechanisms were studied during the dawn rise of glucose in pubertal adolescent patients with IDDM. Two overnight studies were performed in each subject. Patients remained on the same insulin regimen throughout. SUBJECTS Twenty-two diabetic adolescent subjects, aged (mean ± SEM) 14.0 ± 0.4 years, duration of IDDM 7.9 ± 0.8 years, were recruited. Pubertal status was: group 1 (breast stage 1–2; testicular volume < 4–8ml) 3 male and 4 female, group 2 (breast stage 3; testicular volume 10–12 ml) 0 male 4 female, group 3 (breast stage 4–5; testicular volume 15–25 ml) 4 male and 7 female. Height standard deviation score (mean ± SD) (-0.02 ± 099) and dally insulin dose (50.4 ± 3.1 U/day) did not change between studies. There were no differences in HbA1 (study A 11.26 ± 0.45%, study B 11.09 ± 0.42%). METHODS The subjects were admitted for the two studies 0.3 ± 0.03 years apart. Blood samples were taken via an indwelling cannula every 20 minutes between 1900 and 0700 h. MEASUREMENTS GH was assayed every 20 minutes, IGFBP-1, glucose and free Insulin every hour and lGF-I at 0700h. GH, IGFBP-1, IGF-I and free insulin were measured by radioimmunoassay. IGFBPs were also analysed by Western ligand blotting techniques. GH profiles were analysed by Pulsar and results compared by paired Student's t-test. The relations between the dawn rise In glucose and the changes in IGFBP-1, GH and free insulin were examined by multiple linear regression analysis. RESULTS Serum IGFBP-1 levels rose overnight In the two studies (study A, from 9·1 at 2200 to 59 ± 9μg/l at 0700 h; study B, from 10±1 at 2100 to 64 ± 14μg/l at 0700h) whilst insulin levels fell from 47 ± 5 at 2200 to 16 ± 2mU/l at 0700 h (study A) and from 45·5 at 2000 to 14 ± 2mU/l at 0700 h (study B). Glucose levels fell from 16.0 ± 1.0 to 9.3 ± 0.9 mmol/l at 0400h, and then rose to 11.9 ± 1.1 mmol/l at 0700 h during study A, and from 13.4 ± 1.3 to 10.1 ± 1.1 mmol/l at 0400 h and then rose to 13.5 ± 1.0 mmol/l at 0700 h during study B. There were no differences in GH secretion between studies (mean GH levels (mean ± SD) (study A, 15.7 ± 6.6 mU/I; study B, 16.2 ± 7.1 mU/l; correlation within subjects between studies r= 0.77, P < 0.001), sum of GH peaks (study A, 189.9 ± 903 mU/l; study B, 185.8 ±100.2 mU/l; r= 0.57, P= 0.006)). Mean GH levels varied with pubertal stage (group 1,12.1 ± 1.5 mU/l; group 2, 23.3 ± 2.1 mU/I; group 3, 15.3 ± 1.2mU/I). Serum IGF-l levels were not different (study A, 203 ± 12 μg/l; study B, 218 ± 13 μg/l). REGRESSION ANALYSIS The change In plasma glucose between 0200 and 0700 h In both studies related to free insulin, IGFBP-1 and the sum of the GH levels over the preceding hour (log glucose =7.87 + 5.32 log IGFBP-1 (P= 0.0001) ?5.05 log free insulin (P= 0.0001)-1.44 log GH (P= 0.004); R²= 72%). Mean overnight GH levels did not predict the morning rise In plasma glucose. CONCLUSION The morning rise of IGFBP-1 and plasma glucose appear to be related in this group of subjects with IDDM and this was a consistent finding In the two studies. This relation was additive to the effect of Insulin deficiency. No positive relation was noted between GH secretion and glucose levels. These findings support the hypothesis that the increased GH secretion In IDDM Is a marker of IGF-I deficiency rather than a direct causal factor in the increase In insulin resistance. The IGFs may therefore have a direct role In glucose homeostasis via the ‘free’ fraction of circulating IGFs, the availability of which may be modulated by changes in IGFBP-1 levels.     

Serum levels of growth hormone-binding protein and insulin-like growth factor I in children and adolescents with Type 1 (insulin-dependent) diabetes mellitus

Summary Serum levels of insulin-like growth factor I are reduced in patients with Type 1 (insulin-dependent) diabetes mellitus. To evaluate the role of the hepatic growth hormone receptor in the decreased serum concentrations of insulin-like growth factor I, serum levels of the high affinity growth hormone-binding protein, which is qualitatively and quantitatively related to the hepatic growth hormone receptor, and of insulin-like growth factor I were measured in 70 children and adolescents with Type 1 diabetes and 105 healthy control children. Analysis of variance revealed a significant negative effect of Type 1 diabetes on serum levels of the growth hormone-binding protein and of insulin-like growth factor I. In the diabetic patients, serum levels of the growth hormone-binding protein were positively related to body mass index and to insulin dose per kg body weight, and were not influenced by pubertal stage, gender, or plasma levels of haemoglobin A_1c. Serum levels of insulin-like growth factor I increased during early puberty reaching peak levels at midpuberty and decreasing thereafter. No relationship was found between serum levels of growth hormone-binding protein and of insulin-like growth factor I. Our data suggest that decreased liver somatogenic receptor levels, as reflected by the concentrations of circulating growth hormone-binding protein, play a minor role in the suppressed concentrations of circulating insulin-like growth factor I. Post-growth hormone receptor defects or changes in the insulin-like growth factor binding proteins probably contribute more to the lower serum levels of insulin-like growth factor I.     

The effects of recombinant insulin-like growth factor I administration on growth hormone levels and insulin requirements in adolescents with Type 1 (insulin-dependent) diabetes mellitus

Summary Type 1 (insulin-dependent) diabetes mellitus in adolescence is associated with reduced levels of insulin-like growth factor I, elevated growth hormone concentrations and insulin resistance. In order to determine whether restoring insulin-like growth factor I levels to normal might lead to a reduction in growth hormone levels and insulin requirements, we undertook a double-blind placebo controlled study of a single s. c. dose of recombinant insulin-like growth factor I (40 g/kg body weight) in nine late pubertal subjects with Type 1 diabetes. After administration of placebo or insulin-like growth factor I at 18.00 hours, a variable rate insulin infusion was used to maintain euglycaemia overnight. Plasma insulin-like growth factor I, growth hormone, free insulin, and intermediate metabolite concentrations were monitored throughout the study. Recombinant insulin-like growth factor I led to a rise in plasma concentrations which reached a peak at 5.5 h (413.1±28.2 ng/ml, mean±SEM). Mean growth hormone levels between 20.00 and 08.00 hours were significantly reduced after recombinant insulin-like growth factor I (19.4±4.0 compared with 33.6±5.8 mU/l; p=0.01), as were the insulin requirements for euglycaemia (0.25±0.02 compared with 0.31±0.04 mU · kg^–1 · min^–1; p=0.03). Plasma free insulin levels were lower after recombinant insulin-like growth factor I administration (31.9±2.7 compared with 67.9±16.0 mU/l; p=0.001) but no significant differences in ketone or lactate levels were detected. Recombinant insulin-like growth factor I in a s. c. dose of 40 g/kg body weight leads to a significant reduction in overnight growth hormone levels and insulin requirements in adolescents with Type 1 diabetes.     

Effects of intravenous TRH on growth hormone and cortisol serum levels in children and adolescents with insulin dependent diabetes mellitus

The effects of an iv thyrotropin releasing hormone (TRH) bolus on serum growth hormone (GH) and cortisol levels were evaluated in 59 children and adolescents with insulin dependent diabetes mellitus (IDDM) and in 24 healthy, age-matched control subjects. In the IDDM group GH baseline levels sharply rose within 30 min after TRH and successively normalized. On the contrary, TRH injection failed to affect GH serum concentrations in the control group. The GH increase after TRH in IDDM patients was positively correlated to age, but unrelated to other variables, such as sex, pubertal stage, duration of disease, glycemia, glycosylated hemoglobin, thyrotropin and T4 concentrations. Twenty-one out of 59 diabetics and only 1/24 controls exhibited a paradoxical GH response to TRH, arbitrarily defined as a precocious increase (within 30 min), of more than 100% with respect to the baseline value, associated with a GH peak greater than 10 ng/ml. Eighteen IDDM patients underwent a second TRH test 12 to 24 months later and substantially exhibited the same GH pattern documented the first time. The mechanism responsible for such anomalous GH responsiveness to TRH in IDDM is unclear. However, it cannot be attributed to a nonspecific stress reaction, as proven by the lack of a concomitant increase of cortisol serum levels in the same subjects.     

Serum fibroblast growth factor 21 levels in gestational diabetes mellitus in relation to insulin resistance and dyslipidemia

Fibroblast growth factor 21 (FGF21) has beneficial effects on glucose homeostasis and insulin sensitivity. In the current study, we investigated serum concentrations of FGF21 in patients with gestational diabetes mellitus (GDM) as compared with healthy pregnant controls matched for gestational age and fasting insulin. Fibroblast growth factor 21 was determined by enzyme-linked immunosorbent assay in control (n = 80) and GDM (n = 40) patients and correlated to clinical and biochemical measures of renal function, glucose and lipid metabolism, as well as inflammation in both groups. Median maternal serum FGF21 concentrations were not significantly different in subjects with GDM (97.5 ng/L) as compared with healthy pregnant controls (102.9 ng/L). Fibroblast growth factor 21 significantly and positively correlated with markers of insulin resistance (increased homeostasis model assessment of insulin resistance, decreased adiponectin) and dyslipidemia (increased triglycerides, decreased high-density lipoprotein cholesterol) in univariate and multivariate analyses. Furthermore, FGF21 serum levels were highest in patients in the third tertile of homeostasis model assessment of insulin resistance. Fibroblast growth factor 21 is independently associated with markers of insulin resistance and an adverse lipid profile but is not dysregulated in GDM if patients are matched with controls for fasting insulin.     

Serum levels of insulin-like growth factor (IGF) I, II and IGF binding protein in diabetic adolescents treated with continuous subcutaneous insulin infusion

IGF-I and IGF-II as well as the low molecular type of IGF binding protein (IGFPB) were determined in serum from 11 adolescents with insulin-dependent diabetes mellitus (IDDM) during a cross-over study with conventional and continuous subcutaneous insulin infusion (CIT and CSII) therapy. At the onset of the study the mean IGF-I level, 127 +/- 15 ng ml-1, was significantly decreased (P less than 0.001) in comparison with age-matched controls, whereas the mean IGF-II level, 1024 +/- 48 ng ml-1, was increased. A significant correlation (r = 0.70, P less than 0.05) was found between IGF-II and HbA1c levels. The mean morning level of IGFBP, 75 +/- 17 ng ml-1, at the onset of the study, was increased threefold above that in age-matched controls (P less than 0.01). There was a significant correlation between IGFBP and blood glucose values (r = 0.66, P less than 0.05). During CSII therapy a significant decrease (P less than 0.05) of the IGFBP levels was seen in subjects with a decrease in glucose levels, whereas no change was observed in IGF levels. The findings of elevated IGF-II and IGFBP levels and correlations between IGFBP and blood glucose concentration as well as IGF-II and HbA1c levels in adolescents with IDDM indicate that both IGF-II and IGFBP reflect a deranged metabolism caused by inadequate insulin administration.     

Serum levels of angiopoietin-related growth factor in diabetes mellitus and chronic hemodialysis

Angiopoietin-related growth factor (AGF) was recently introduced as a novel liver-derived protein that antagonizes obesity and insulin resistance. In the current study, we investigated circulating AGF levels in relation to renal function and type 2 diabetes mellitus (T2DM). Angiopoietin-related growth factor was determined by enzyme-linked immunosorbent assay in subjects with a glomerular filtration rate greater than 50 mL/min (n = 60, 30 diabetic and 30 nondiabetic) and in patients on chronic hemodialysis (CD; n = 60, 32 diabetic and 28 nondiabetic). Furthermore, AGF was correlated to clinical and biochemical measures of renal function, glucose and lipid metabolism, as well as inflammation. Median serum AGF levels were significantly lower in CD patients (125.9 ± 96.3 μg/L) as compared with subjects with a glomerular filtration rate greater than 50 mL/min (164.0 ± 95.4 μg/L) (P < .05). Furthermore, AGF serum levels were significantly increased in diabetic patients (161.7 ± 114.2 μg/L) as compared with nondiabetic subjects (123.0 ± 88.2 μg/L) (P < .01). Moreover, CD negatively and T2DM positively predicted AGF concentrations in multiple regression analysis. In addition, fasting serum glucose was independently and positively correlated with circulating AGF in all patients and controls. Our results suggest that renal dysfunction is negatively and T2DM is positively associated with AGF serum levels. Further studies are needed to better elucidate the physiologic significance of circulating AGF in human disease.     

Limited joint mobility in children and adolescents with insulin dependent diabetes mellitus.

Joint mobility was studied in 70 children with insulin dependent diabetes mellitus aged 8-17 years, and the prevalence of limited joint mobility (LJM) was found to be 31% (22/70). This figure fell to only 7% (5/70) when an alternative method of assessment was used. A high number of non-diabetic, non-sibling controls (6/51 (12%] were found to have LJM. There was a trend towards an increasing prevalence of LJM with increasing age and duration of diabetes, but it was also found in patients with recent onset diabetes. A large proportion of prepubertal patients were noted to have LJM. No correlation was found between LJM and either short stature or diabetic control. There is a need for standardisation of the methods used to define and stage LJM in diabetic patients, and the significance of this clinical finding remains unclear.     

Loss of the normal relationships between growth hormone, growth hormone-binding protein and insulin-like growth factor-I in adolescents with insulin-dependent diabetes mellitus

OBJECTIVE It has been proposed that the dissociation between growth hormone secretion and insulin-like growth factor-I (IGF-I) concentrations in insulin-dependent diabetes mellitus arises because of partial resistance at the GH receptor. In order to explore this hypothesis further we have examined the relations between IGF-I, GH-binding protein (GHBP), and GH secretion in normal subjects and patients with diabetes during puberty. DESIGN AND SUBJECTS Blood samples for the estimation of IGF-I and GHBP levels were obtained from 104 patients with diabetes and 89 puberty matched controls. Thirty-four of the controls and 42 of the patients with diabetes also underwent an overnight GH secretory profile with measurements of GH every 15–20 minutes between 2000 and 0800 h. RESULTS In multivariate analysis using sex, puberty stage, and presence or absence of diabetes as dependent variables, diabetes was associated with increased GH levels (F= 23·04, P < 0·001), reduced IGF-I (F= 10·89, P < 0·001), and reduced GHBP levels (F= 31·36, P < 0·001). A negative relation between GH and GHBP levels (r= -0·44, P < 0·01) was found in normal subjects but this was absent in those with diabetes. Both GHBP and IGF-l levels in the diabetic subjects were correlated with total insulin dose (r= 0·4, P < 0·001, and r= 0·46, P < 0·001, respectively). Yet there was no direct correlation between GHBP and IGF-I concentrations. The variation in IGF-I levels was also related to glycosylated haemoglobin levels in the diabetics (r= -0·27, P= 0·01). In a stepwise multiple regression analysis insulin dose contributed 23%, HbA₁ 4·4% and C-peptide levels 3·7% to the variation in IGF-I levels. CONCLUSIONS In adolescents with insulin dependent diabetes mellitus, the elevated OH concentrations are associated with low circulating IGF-l and GHBP concentrations and the normal reciprocal relation between GHBP and GH is no longer evident. Although IGF-I and GHBP are both related to insulin dose, there is no direct correlation between these variables. This may indicate that GHBP reflects GH receptor numbers but not necessarily post receptor events, and the weak positive correlation between GH and IGF-I indicates that increased growth hormone secretion may compensate for reduced receptor numbers.     

Serum insulin-like growth factor II in chronic liver disease

Insulin-like growth factor II is secreted primarily by the liver and is reported to be transcribed in many primary hepatocellular carcinoma (PHC) cell lines. We have studied diagnostic significance of serum IGF-II in chronic liver diseases using specific enzyme immunoassay. Serum IGF-II levels (mean +/- SE) were decreased in chronic hepatitis (538 +/- 51 ng/ml; N = 29), liver cirrhosis (427 +/- 45; 50) and PHC (260 +/- 41; 17) compared to controls (830 +/- 49; 57). Serum IGF-II was not different from controls in any of nonhepatic diseases such as diabetes (1032 +/- 97; 19) pancreatic cancer (1413 +/- 282; 8), chronic pancreatitis (999 +/- 126; 17), peptic ulcer (1186 +/- 43; 11), irritable bowel syndrome (1002 +/- 109; 12), gastrointestinal tract cancer (1250 +/- 216; 21) and chronic renal failure (733 +/- 135; 14). In liver diseases serum IGF-II showed a significant correlation with liver function test (negative with retention of indocyanine green and total bile acids; positive with albumin, thrombo-test, and cholinesterase). These results suggest that serum IGF-II reflects a reduced production of IGF-II in the liver and that it can be an index for the residual capacity of liver function.     

Expression of insulin-like growth factor II and receptors for insulin-like growth factor II, insulin-like growth factor I and insulin in isolated and cultured rat hepatocytes.

Insulin-like growth factor II is believed to play an important role in fetal growth and development. The insulin-like growth factor II gene expression is tissue specific and developmentally regulated. We have previously shown an enhanced level of insulin-like growth factor II messenger RNA and protein in human hepatocellular carcinomas. This led to the suggestion that hepatocytes might be involved in insulin-like growth factor II expression. However, previous studies based on in situ hybridization only showed insulin-like growth factor II messenger RNA in liver sinusoidal cells. This paper reports on the analysis of the expression of insulin-like growth factor II and insulin-like growth factor II, insulin-like growth factor I and insulin receptor messenger RNAs in vivo in isolated rat hepatocytes at various stages of development and in vitro in adult rat hepatocytes primary culture. Our study indicates that isolated rat hepatocytes synthesize insulin-like growth factor II messenger RNA with a switch between fetal and adult messenger RNA profiles occurring 21 days after birth. In addition, adult rat hepatocytes in culture expressed insulin-like growth factor II messenger RNA and protein. Insulin-like growth factor II, insulin-like growth factor I and insulin receptor messenger RNAs were also detected. Therefore these results are consistent with the hypothesis that insulin-like growth factor II acts as an autocrine growth factor for hepatocytes in addition to having a paracrine effect. They also indicate that primary culture of hepatocytes is a good model for further studies on insulin-like growth factor II gene regulation.     

Changes in growth hormone concentrations during puberty in adolescents with insulin dependent diabetes

OBJECTIVE--To document the changes in pulsatile growth hormone secretion in diabetic adolescents during puberty, and to investigate their relationship to both metabolic control and stature. DESIGN--Auxological parameters, overnight growth hormone secretion, fasting IGF-I, hourly glucose and metabolic control were assessed in a group of adolescents with diabetes. PATIENTS--Fifty-two diabetic adolescents (28 males and 24 females) at different pubertal stages and with varying degrees of metabolic control were studied. Ten of those with poor diabetic control were studied on two occasions. MEASUREMENTS--Height and weight measurements, pubertal staging, growth velocity data and bone age estimation were obtained on all the patients. Overnight growth hormone profiles (Pulsar program analysis), glycosylated haemoglobin and fasting IGF-I were performed on all the subjects. Hourly overnight glucose measurements were also obtained on the ten subjects who had two overnight growth hormone studies. RESULTS--For the whole diabetic growth, GH area under curve (AUC) was maximal in late puberty (pubertal stage 4), and was paralleled by maximal GH peak amplitude. No relationship between GH-AUC and metabolic control was demonstrated. No difference in GH parameters was demonstrated between the male and female subgroups. The relationship between growth hormone secretory parameters and stature was not significant. However, GH-AUC was significantly correlated with growth velocity in the males but not the females. CONCLUSIONS--The pattern of GH secretion in adolescents with diabetes parallels that seen in normal adolescents during puberty, with increases in GH concentration associated with increased GH pulse amplitude. The degree of metabolic control had no effect on this pattern and there was no relationship between GH secretory parameters and stature.     

The relationship between overnight GH levels and insulin concentrations in adolescents with insulin-dependent diabetes mellitus (IDDM) and the impact of recombinant human insulin-like growth factor I (rhIGF-I)

OBJECTIVE We examined the relationship between GH concentrations and free insulin concentrations, used as an index of insulin sensitivity, before and after recombinant human insulin-like growth factor I (rhIGF-I) administration in adolescents with insulin-dependent diabetes mellitus (IDDM). DESIGN AND PATIENTS Growth hormone concentrations were assessed by a peak detection programme (Pulsar) on a control night (2000 h–0800 h) and a night when rhIGF-I was administered in a subcutaneous dose of 40 μg/kg at 1800 h to 16 adolescent subjects. Stable euglycaemia was maintained by a continuous intravenous insulin infusion and changes in free insulin levels on the two nights were compared with growth hormone data. RESULTS Mean overnight GH concentrations (2000 h–0800 h) on the control night were positively related to glycated haemoglobin (HbA1) concentrations (r=0.63; P<0.01) and were reduced following rhIGF-I administration (24.9±3.6 mU/l on the control night versus 17.4±2.2 mU/l after administration, P=0.01). The mean GH pulse amplitude on the control night was related to the change in GH levels after rhIGF-I (r_s=?0.66, P<0.001). Multiple regression analysis revealed that mean GH pulse amplitude was the only determinant of free insulin concentrations (0500 h–0700 h) on both study nights (P<0.01). The percentage change in mean growth hormone pulse amplitude between the two nights was related to the percentage reduction in free insulin concentrations (r=0.53, P=0.03). CONCLUSIONS Growth hormone pulse amplitude is related to early morning insulin sensitivity in adolescents with IDDM on control nights and after rhIGF-I administration. The reduction in insulin levels following rhIGF-I may be linked to the change in GH pulse amplitude and not just to direct insulin-like actions. Individuals with the higher GH (and thus HbA1 levels) were most sensitive to the GH-suppressive effects of rhIGF-I.     

Serum levels of insulin-like growth factor (IGF) and IGF-binding protein in constitutionally short children and adolescents

Serum insulin-like growth factor (IGF) and IGF-binding protein (IGF-bp) levels were studied in 92 constitutionally short children and adolescents (height less than mean for age -2 SD) and in 13 subjects after completion of growth. IGF levels increased with age in a manner similar to that in normal subjects, but at lower levels (P less than 0.001). The values were 0.41 +/- 0.03 SEM U/ml in 1 to 5 year old children, 0.72 +/- 0.03 U/ml in 6- to 16 year old prepubescent children and 0.95 +/- 0.05 U/ml during puberty. IGF-bp levels developed in a similar way, the values being 0.45 +/- 0.06, 0.61 +/- 0.04 and 0.85 +/- 0.06 U/ml, respectively, for the three periods considered. Both IGF and IGF-bp levels in each of the three groups were significantly lower than those in normal subjects at the same stage of development. After fusion of the epiphyses, IGF and IGF-bp levels were within the normal range. A longitudinal study was undertaken in 15 subjects, showing increases in height corresponding with increases in IGF levels. For all the subjects studied during their growth period, there was a correlation between height age and IGF levels (r = 0.64, P less than 0.001). All the subjects exhibited a normal rise in GH levels following stimulation. Although the possibility of quantitative or qualitative disorders of GH biosynthesis cannot be excluded in some of the cases, our data are compatible with the hypothesis that the growth retardation observed in constitutionally short children results, at least in part, from insufficient IGF production during post-natal growth.     

Abnormal regulation of insulin-like growth factor binding proteins in adolescents with insulin-dependent diabetes.

We have measured fasting 0800 h insulin-like growth factor binding proteins (IGFBP)-1 and IGFBP-3, in 52 diabetic adolescents and 74 puberty-matched control subjects with short stature and normal hormonal status. We have also measured overnight hourly profiles of IGFBP-1, glucose, free insulin, and GH in 12 of the diabetic adolescents. With advancing age and pubertal status, IGFBP-1 declined and IGFBP-3 increased significantly in the control, but not the diabetic group. Fasting IGFBP-1 levels were elevated 4-fold compared to controls. Median IGFBP-3 was significantly lower in the diabetic compared to the control group in pubertal stages III and V. Elevated IGFBP-1 was significantly correlated with metabolic control in poorly controlled subjects (mean 12-month glycosylated haemoglobin greater than 8.5%). In the overnight profiles, mean hourly IGFBP-1 was inversely related to insulin, but not glucose. As free insulin levels declined, IGFBP-1 rose, associated with rising predawn blood sugars. The integrated 3-h IGFBP-1 value (0500-0800 h) was significantly correlated with the corresponding glucose integrated value. IGFBP-1 area under the curve for the whole overnight profile was significantly correlated with glycosylated hemoglobin in 11 of the 12 subjects. IGFBP-1 from diabetic adolescents has been shown to inhibit IGF-I bioactivity. We postulate that IGFBP-1 may have a role in growth impairment of poorly controlled diabetes and may contribute to the dawn phenomenon.     

Serum insulin-like growth factor-I is negatively associated with serum adiponectin in type 2 diabetes mellitus

Background

Although insulin-like growth factor-I (IGF-I) and dehydroepiandrosterone-sulfate (DHEA-S) are involved in age-related diseases such as cardiovascular disease and diabetes mellitus, the association of these hormones with serum adiponectin level is still unclear.

Objective and methods

To investigate the association between serum IGF-I and DHEA-S versus adiponectin, we conducted a cross-sectional study of 348 Japanese men with type 2 diabetes mellitus and examined their relationships. Serum total adiponectin level was measured by an ELISA kit.

Results

Simple correlation analysis showed that patients' age and duration of diabetes were negatively correlated with IGF-I and DHEA-S (p < 0.01) and positively with adiponectin (p < 0.01), while body mass index (BMI) was positively correlated with IGF-I and DHEA-S (p < 0.001) and negatively with adiponectin (p < 0.001). IGF-I was negatively correlated with adiponectin (r = − 0.25, p < 0.001) and DHEA-S was negatively correlated with adiponectin and HbA1c (r = − 0.17, p = 0.003 and r = − 0.12, p = 0.027, respectively). In multiple regression analysis adjusted for age, duration of diabetes, BMI, and serum creatinine, HbA1c was negatively associated with IGF-I and DHEA-S (β = − 0.12, p = 0.036 and β = − 0.22, p < 0.001, respectively). Adiponectin was negatively associated with IGF-I (β = − 0.15, p = 0.013), but not DHEA-S. Moreover, this association was still significant after additional adjustment for HbA1c (β = − 0.18, p = 0.005).

Conclusions

Present cross-sectional study for the first time showed a negative association of serum IGF-I with serum adiponectin in Japanese men with type 2 diabetes independent of age, duration of diabetes, BMI, renal function, and HbA1c.