Recombinant human insulin-like growth factor-I: a therapeutic challenge for diabetes mellitus

Diabetologia - Insulin-like growth factor I (IGF I) is an endocrine hormone that mediates most of the effects of pituitary growth hormone. Other important regulatory factors of serum IGF I levels...     

Recombinant human insulin-like growth factor-I treatment inhibits gluconeogenesis in a transgenic mouse model of type 2 diabetes mellitus

IGF-I and insulin are structurally related polypeptides that mediate a similar pattern of biological effects via receptors that display considerably homology. Administration of recombinant human IGF-I (rhIGF-I) has been proven to improve glucose control and liver and muscle insulin sensitivity in patients with type 2 diabetes mellitus (DM). The effect of rhIGF-I treatment was evaluated in a mouse model of type 2 DM (MKR mouse), which expresses a dominant-negative form of the human IGF-I receptor under the control of the muscle creatine kinase promoter specifically in skeletal muscle. MKR mice have impaired IGF-I and insulin signaling in skeletal muscle, leading to severe insulin resistance in muscle, liver, and fat, developing type 2 DM at 5 wk of age. Six-week-old MKR mice were treated with either saline or rhIGF-I for 3 wk. Blood glucose levels were decreased in response to rhIGF-I treatment in MKR mice. rhIGF-I treatment also increased body weight in MKR with concomitant changes in body composition such as a decrease in fat mass and an increase in lean body mass. Insulin, fatty acid, and triglyceride levels were not affected by rhIGF-I, nor were insulin or glucose tolerance in MKR mice. Hyperinsulinemic-euglycemic clamp analysis demonstrated no improvement in overall insulin sensitivity. Pyruvate and glutamine tolerance tests proved that there was a decrease in the rate of glucose appearance in MKR mice treated with rhIGF-I, suggesting a reduction in the gluconeogenic capacity of liver, kidney, and small intestine. Taken together these results demonstrate that the improvement of the hyperglycemia was achieved by inhibition of gluconeogenesis rather than an improvement in insulin sensitivity. Also, these results suggest that a functional IGF-I receptor in skeletal muscle is required for IGF-I to improve insulin sensitivity in this mouse model of type 2 DM.     

Effects of recombinant human insulin-like growth factor-I (rhIGF-I) on total and free IGF-I concentrations, IGF-binding proteins, and glycemic response in humans.

To examine the effects of repeated administration of recombinant human insulin-like growth factor-I (rhIGF-I) on IGF-I levels, free IGF-I pharmacokinetics, glycemic response, and IGF-binding proteins (IGFBP), we administered rhIGF-I (0.03 mg/kg iv bolus) to 12 healthy males each morning for 5 consecutive days. Serum was collected over 24 h on days 1 and 5 for measurement of total and free IGF-I, glucose, insulin, and IGFBP. Total IGF-I was measured by RIA after acid/ethanol extraction. Free IGF-I was separated from binding protein-complexed IGF-I using size exclusion high performance liquid chromatography before measurement by RIA. IGFBP were quantitated by optical densitometry of Western ligand blots. Total IGF-I increased significantly from 0-24 h after administration on day 1 (mean +/- SD, micrograms/L: 120 +/- 44 to 166 +/- 51, P = 0.0002) but did not increase significantly from 24 h on day 1 to 0 h on day 5 (166 +/- 51 to 178 +/- 62) or from 0-24 h on day 5 (178 +/- 62 to 209 +/- 89). The area under the total IGF-I concentration curve was greater on day 5 than day 1 (311 +/- 99 min.g/L vs. 249 +/- 77, P = 0.0001). There were no significant differences in free IGF-I concentration or pharmacokinetic parameters or in the degree or timing of hypoglycemia between days 1 and 5. Plasma insulin levels decreased significantly following rhIGF-I administration (day 1 baseline: 53 +/- 11 pmol/L, nadir: 18 +/- 6 pmol/L at 30 min, P = 0.003); day 5 baseline: 47 +/- 15 pmol/L, nadir: 16 +/- 8 pmol/L at 30 min, P = 0.0003. Western ligand blotting revealed the transient appearance of a 30-kilodalton band which migrates in a manner similar to IGFBP-1. This band was undetectable at baseline, peaked between 150 and 210 min after rhIGF-I administration, and diminished by 480-600 min. The response was similar on days 1 and 5. There were no substantial changes in the serum levels of any other IGFBP. In summary, repeated iv bolus administration of rhIGF-I increased the level of total circulating IGF-I without changing free IGF-I disposition or glycemic response. A 30-kilodalton IGFBP band, most likely IGFBP-1, appeared transiently following rhIGF-I administration, probably as a result of suppression of insulin levels. IGFBP-2, -3, and -4 were unaffected.     

Effects of low-dose recombinant human insulin-like growth factor-I on insulin sensitivity, growth hormone and glucagon levels in young adults with insulin-dependent diabetes mellitus

Despite recent interest in the therapeutic potential of recombinant human insulin-like growth factor-I (rhIGF-I) in the treatment of diabetes mellitus, its mechanism of action is still not defined. We have studied the effects of low-dose bolus subcutaneous rhIGF-I (40 μg/kg and 20 μg/kg) on insulin sensitivity, growth hormone (GH) and glucagon levels in seven young adults with insulin-dependent diabetes mellitus (IDDM) using a randomized double-blind placebo-controlled crossover study design. Each was subjected to a euglycemic clamp (5 mmol/L) protocol consisting of a variable-rate insulin infusion clamp (6:00 to 8:00 ) followed by a two-dose hyperinsulinemic clamp (insulin infusion of 0.75 mU · kg⁻¹ · min⁻¹ from 8 to 10 and 1.5 mU · kg⁻¹ · min⁻¹ from 10 to 12 noon) incorporating [6,6 ²H₂]glucose tracer for determination of glucose production/utilization rates. Following rhIGF-I administration, the serum IGF-I level (mean ± SEM) increased (40 μg/kg, 655 ± 90 ng/mL, P < .001; 20 μg/kg, 472 ± 67 ng/mL, P < .001; placebo, 258 ± 51 ng/mL). Dose-related reductions in insulin were observed during the period of steady-state euglycemia (1 to 8 ) (40 μg/kg, 48 ± 5 pmol/L, P = .01; 20 μg/kg, 58 ± 8 pmol/L, P = .03; placebo, 72 ± 8 pmol/L). The mean overnight GH level (40 μg/kg, 9.1 ± 1.4 mU/L, P = .04; 20 μg/kg, 9.6 ± 2.0 mU/L, P = .12; placebo, 11.3 ± 1.7 mU/L) and GH pulse amplitude (40 μg/kg, 18.8 ± 2.9 mU/L, P = .04; 20 μg/kg, 17.0 ± 3.4 mU/L, P> .05; placebo, 23.0 ± 3.7 mU/L) were also reduced. No differences in glucagon, IGF binding protein-1 (IGFBP-1), acetoacetate, or β-hydroxybutyrate levels were found. During the hyperinsulinemic clamp conditions, no differences in glucose utilization were noted, whereas hepatic glucose production was reduced by rhIGF-I 40 μg/kg (P = .05). Our data demonstrate that in subjects with IDDM, low-dose subcutaneous rhIGF-I leads to a dose-dependent reduction in the insulin level for euglycemia overnight that parallels the decrease in overnight GH levels, but glucagon and IGFBP-1 levels remain unchanged. The decreases in hepatic glucose production during the hyperinsulinemic clamp study observed the following day are likely related to GH suppression, although a direct effect by rhIGF-I cannot be entirely discounted.     

Sexual dimorphism in growth and insulin-like growth factor-I in children with type 1 diabetes mellitus

ObjectiveImpaired linear growth and reduced IGF-I levels in children with type 1 diabetes (T1DM) have been related to poor metabolic control. The aim of this study was to identify additional factors which may negatively affect growth and IGF system in patients with T1DM.DesignNinety-one T1DM children (54 males, age = : 11.73 ± 3 years, disease duration = 5.6 ± 2.1 years) were studied. All children were on intensive insulin therapy: 62 children were on multiple injection therapy (MI) and 29 children on continuous subcutaneous insulin infusion (CSII).ResultsHeight velocity (HV) SDS and IGF-I levels were higher in females and in pubertal children [HV SDS: females = 0.6 ± 2.4 vs males = − 0.45 ± 2.3 (p = 0.04); IGF-I SDS: females = − 1.09 ± 0.58 vs males = − 1.4 ± 0.6 (p = 0.02); IGF-I/IGFBP-3 molar ratio: females = 0.25 ± 0.1 vs males = 0.21 ± 0.08 (p = 0.04); IGF-I SDS: pre-pubertal = − 1.58 ± 0.46 vs pubertal = − 1.15 ± 0.65 (p < 0.001); IGF-I/IGFBP-3 molar ratio: pre-pubertal = 0.16 ± 0.08 vs pubertal = 0.26 ± 0.09 (p < 0.001)]. No differences between children on CSII or MI therapy were found. IGF-I SDS was positively related to C peptide level (p < 0.001), puberty (p < 0.001) and female gender (p = 0.02) and negatively related to HbA1c (p = 0.04). IGF-I/IGFBP-3 molar ratio was positively affected by C peptide level (p < 0.001), puberty (p < 0.001) and daily insulin dose (p < 0.001).ConclusionsOur results indicate that despite intensive insulin therapy, T1DM still negatively affects IGF-I secretion and linear growth. Growth impairment is more severe in males and primarily related to poor glycemic control and loss of the residual beta cell mass.     

Effects of recombinant insulin-like growth factor-I (IGF-I) and growth hormone on serum IGF-binding proteins in calorically restricted adults.

To determine the effects of exogenous insulin-like growth factor-I (IGF-I) and GH on IGF-binding proteins (IGFBP)-1, -2, and -3, six healthy nonobese adult volunteers underwent two 2-week periods of diet restriction (20 Cal/kg.day), and during the last 6 days of the first period received either IGF-I (12 micrograms/kg.h by iv infusion over 16 h) or GH (0.05 mg/kg.day by sc injection). During the second 2-week study period, the alternate hormone was given. IGFBP-1 and -2 concentrations were determined by specific RIA, and changes in IGFBP-3 were assessed by ligand blotting. Free IGF-I concentrations were measured by size-exclusion high pressure liquid chromatography, followed by RIA. Diet restriction alone did not affect either IGFBP-1 or -2 significantly. IGF-I treatment increased IGFBP-1 from 78 +/- 46 ng/mL (mean pretreatment) to 137 +/- 64 ng/mL (P less than 0.001; mean for the last 4 days of IGF-I). IGF-I also caused an increase in IGFBP-2 from 315 +/- 136 to 675 +/- 304 ng/mL (P less than 0.001). GH injections caused a modest decline in IGFBP-1 concentrations but had no effect on IGFBP-2 concentrations. By ligand blotting, both IGF-I and GH caused a modest increase in IGFBP-3 band intensity. In three subjects diet restriction alone caused a small decrease in IGFBP-3 hand intensity, and this was reversed by hormone treatment. Free IGF-I concentrations in serum were increased from 1.6% to 4.4% of the total IGF-I during IGF-I infusions. GH injections caused a smaller increase in free IGF-I concentrations. The results show significant increases in IGFBP-1 and -2 during IGF-I infusion. The change in IGFBP-3, while significant, is quantitatively less than that in experimental animals that have been given IGF-I while undergoing dietary restriction. The net effect of the changes in these three forms of IGFBPs is not sufficient to maintain a normal IGF-I-binding capacity in serum, because free IGF-I levels were increased disproportionately during the IGF-I infusions. Because hypoglycemia was noted in these subjects despite insulin suppression, these alterations in IGFBPs might have changed the tissue bioavailability of IGF-I and facilitated its hypoglycemic effects.     

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.     

The role of IGF-binding proteins in mediating the effects of recombinant human IGF-I on insulin requirements in type 1 diabetes mellitus

To determine the role of IGF-binding proteins in mediating the direct effects of recombinant human IGF-I on insulin requirements in type 1(insulin-dependent) diabetes mellitus, overnight changes in IGF-I, IGF-II, and IGF-binding protein-1, -2, and -3, collected under euglycemic conditions, were compared in nine subjects after double blind, randomized, sc administration of recombinant human IGF-I (40 microg/kg) or placebo at 1800 h. On both nights a somatostatin analog infusion (300 ng/kg x h) suppressed endogenous GH production, and three timed discrete GH pulses (total, 0.029 IU/kg x night) ensured identical GH levels. After recombinant human IGF-I administration, IGF-I levels and the IGF-I/IGF-binding protein-3 ratio increased [mean +/- SEM:IGF-I, 401 +/- 22 ng/ml; placebo, 256 +/- 20 ng/ml (P = 0.0002); IGF-I, 0.108 +/- 0.006; placebo, 0.074 +/- 0.004 (P = 0.0003), respectively], and insulin requirements decreased (IGF-I, 0.12 +/- 0.03; placebo, 0.23 +/- 0.03 U/kg x min; P = 0.008). The normal within-individual inverse relationships between insulin and IGF-binding protein-1 levels were observed (lag time 2 h: r = -0.34; P < 0.01). Yet despite reduced free insulin levels (8.5 +/- 1.5; placebo, 12.2 +/- 1.2 mU/liter; P = 0.03), IGF-binding protein-1 levels were reduced after recombinant human IGF-I administration (53.7 +/- 6.8; placebo, 82.2 +/- 11.8 ng/ml; P = 0.008). The largest reductions in free insulin levels after recombinant human IGF-I and thus putative improvement in insulin sensitivity occurred in subjects with the smallest increase in the plasma IGF-I/IGF-binding protein-3 ratio (r = 0.7; P = 0.03). Taken together, these data are consistent with the hypothesis that transcapillary movement of IGF-I (perhaps mediated by IGF-binding protein-1), out of the circulation facilitates altered insulin sensitivity. These data have important implications for risk-benefit assessment of recombinant human IGF-I therapy in type 1 diabetes mellitus.     

Short and long term effects of growth hormone on circulating levels of insulin-like growth factor-I (IGF-I), IGF-binding protein-1, and insulin: a placebo-controlled study.

The short and long term effects of GH on serum concentrations of insulin-like growth factor-I (IGF-I), IGF-binding protein-1 (IGFBP-1), and insulin were investigated in women participating in an in vitro fertilization program. In this placebo-controlled study, sterile saline (eight women) or 24 IU GH (eight women) were given im on alternate days, starting on cycle day 4, in combination with GnRH and human menopausal gonadotropin. IGFBP-1 levels decreased significantly during the first 4 h after GH administration, whereas no significant changes were seen in the placebo group. The concentrations of serum IGF-I and insulin did not change during 4 h after GH injection. During the 11-day follow-up period, serum levels of both IGF-I and insulin were significantly higher in GH-treated than in placebo-treated women. These results suggest that the serum concentration of IGFBP-1 is not completely GH independent. They also support the earlier findings that long term treatment with GH increases serum IGF-I and insulin levels.     

Insulin and insulin-like growth factors (IGFs) stimulate production of IGF-binding proteins by ovarian granulosa cells.

Ligand blot analysis of granulosa cell (GC)-conditioned culture medium revealed several easily measurable insulin-like growth factor (IGF)-binding proteins (IGFBPs), including IGFBP-3 [40-44 kilodaltons (kDa)] and IGFBP-2 (34 kDa). In the present study, IGF-I, in a dose-dependent manner, significantly stimulated the production of these IGFBPs. Insulin, but not IGF-II, mimicked IGF-I's action on IGFBP-3 and -2 production, but was less potent. The synthetic IGF, long R3-IGF-I, which has very low affinity for IGFBPs and only slightly reduced affinity for the IGF-I (type I) receptor, had significantly greater potency in stimulating IGFBP-3 and -2 production compared to IGF-I. Des-(1-3)-IGF-I had similar effects. IGF-I, IGF-II, and the IGF-I analogs, but not insulin, also induced production of an unidentified 30-kDa IGFBP not normally detectable in these cultures. However, in the presence of epidermal growth factor (which was without independent effect on the 30-kDa IGFBP), insulin also induced this 30-kDa IGFBP. By Northern analysis the expression of IGFBP-3 mRNA was found to be significantly stimulated by IGF-I. In summary, insulin stimulated IGFBP-3 and -2 production in a manner that mimics that of IGF-I and the more potent long R3-IGF-I. However, its low potency suggested that IGFBP production is regulated via the IGF-I (type I) receptor. The much higher potency of long R3-IGF-I compared to that of IGF-I suggests that the IGFBPs themselves modulate the action of IGFs by sequestering exogenous IGFs. Thus, one cellular response to IGF stimulation is the production of IGFBPs, which, in turn, reduce or negate the biological activity of the IGFs. The effects of insulin-like peptides are exerted at least in part by increasing levels of mRNA for specific BPs.     

Relationship between non-enzymatic glycosylation and changes in serum insulin-like growth factor-1 (IGF-1) and IGF-binding protein-3 levels in patients with type 2 diabetes mellitus

The possible occurrence of increased non-enzymatic glycosylation of serum insulin-like growth factor binding protein-3 (IGFBP-3) in vivo and the changes that would simultaneously occur in serum levels of IGFBP-3 and insulin-like growth factor-1 (IGF-I) were investigated. We measured levels of IGF-I and IGFBP-3 and the degree of glycation of total serum protein and IGFBP-3, in serum samples obtained from patients with poorly controlled non-insulin-dependent diabetes (type 2) and from age-matched non-diabetic controls. Type 2 diabetic patients had significantly higher glycated serum protein (GlyP) levels. GlyP significantly correlated with age in the control (r = 0.315, P<0.05) but not in the type 2 diabetes group. Control and diabetic subjects had comparable serum IGF-I levels and in both groups IGF-I levels tended to decrease with age (r = –0.567, P<0.001 and r = –0.465, P<0.05 for control and type 2 diabetic subjects, respectively). In the type 2 diabetes group, IGF-I levels showed a negative correlation with serum GlyP values (r = –0.476, P<0.05). Type 2 diabetic and control patients had comparable serum IGFBP-3 levels, which were significantly higher in diabetic patients in the older age subgroups. A negative correlation was found between IGFBP-3 levels and age in the control (r = –0.705, P<0.001) and in the type 2 diabetes groups (r = –0.463, P<0.05). A significant negative correlation was found between IGFBP-3 levels and GlyP in control (r = –0.449, P<0.002) but not in type 2 diabetic subjects. The mean glycated IGFBP-3 (GlyIGFBP-3) levels were higher in the oldest type 2 diabetic patients. In these patients, GlyIGFBP-3 was negatively associated with IGF-I levels (r = –0.447, P<0.05). The IGF-I/IGFBP-3 molar ratio was significantly reduced in the 46–60-year-old type 2 diabetic group, whereas the IGF-I/IGFBP-3 ratio was positively and significantly correlated with GlyP levels only in the control group (r = 0.489, P<0.01). Our results show that: a) increased non-enzymatic glycosylation of IGFBP-3 occurs in vivo; and b) this effect is accompanied by an increase in IGFBP-3 levels. These results suggest that the IGF-I/IGFBP-3 system is another target for the metabolic derangements of type 2 diabetes. Its alterations might play a role in diabetic complications. Received: 22 September 1997 / Accepted in revised form: 30 April 1998     

Insulin-like growth factor-I treatment of growth disorders, diabetes mellitus and insulin resistance.

Insulin-like growth factor I (IGF-I) has many potential therapeutic uses because of its varied effects--growth promotion, insulin-like influence on glucose metabolism, and neuroprotection resulting from cell-proliferative and antiapoptotic properties--but they have not been investigated systematically in clinical situations. The growth-promoting effect of recombinant human IGF-I (rhIGF-I) in the extensively studied growth hormone insensitivity syndrome (GHIS; Laron syndrome) signifies an endocrine role for the GH-IGF system. The metabolism of (adult) patients with severe insulin resistance is improved by rhIGF-I, which--together with insulin therapy--also improves metabolic control in type 1 and 2 diabetes. Further studies on IGF-I metabolic effects and growing understanding of the IGF-I-IGF-binding protein system could open new therapeutic avenues.     

Gene expression and serum levels of insulin-like growth factors (IGFs) and IGF-binding proteins in a case of non-islet cell tumour hypoglycaemia

We describe a case of non-islet cell tumour hypoglycaemia (NICTH) associated with a renal cell carcinoma. Serum insulin-like growth factors (IGFs) (including IGF-II E peptide), IGF-binding proteins (IGFBPs), insulin and C-peptide were measured before and after surgical removal of the tumour. IGFBPs were visualized by Western ligand blotting. Preoperatively 'big' IGF-II and IGFBP-2 levels were raised. IGF-I, IGFBP-1 and IGFBP-3 were low, while insulin, C-peptide and GH were undetectable. These changes were reversed by 2 days postoperatively. Protease assays showed little IGFBP-3 protease activity preoperatively. Preoperatively, neutral chromatography demonstrated most of the immunoassayable IGFBP-3 in a high molecular weight form with a small amount of IGF-II. Most of the IGF-II and big IGF-II eluted in lower molecular weight forms. Postoperative samples showed a shift in IGF-II which became increasingly associated with IGFBP-3 in both low and high molecular weight complexes. By Northern blotting, expression of all species of IGF-II mRNA in the tumour was 10-fold greater than in normal human liver. The tumour did not express IGFBP-1 or IGFBP-2. IGFBP-3 was expressed in small amounts, while the expression of IGFBP-4 was two-fold higher than in liver. In conclusion, we have confirmed high levels of big IGF-II and IGFBP-2 in NICTH, changes which are reversed postoperatively. The IGF-II is derived from the tumour which overexpresses these genes but IGFBP-2 probably arises from extratumour upregulation.     

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.     

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.     

Reduced serum insulin-like growth factor-1 (IGF-1) and IGF-binding protein-3 levels in adults with inflammatory bowel disease

In the present study, the changes in circulating IGF-1 and its binding protein IGFBP-3 were determined in adult patients with active inflammatory bowel disease (IBD) in order to assess the effect of this inflammatory condition on the IGF system. IGF-1 and IGFBP-3, as well as interleukin-6 (IL-6) were measured in serum obtained from 22 consecutive newly diagnosed patients (mean age 41.3 years) with active IBD, including 10 patients with Crohn's disease (CD), and 12 with ulcerative colitis (UC). For comparison the same parameters were determined in 30 healthy volunteers matched for age, sex and Body Mass Index (BMI). Serum IGF-1 and IGFBP-3 levels were similar in the two subgroups of patients and the values from all patients were combined for comparison with those from the control group. The mean (+/- SD) serum IGF-1 concentration (178 +/- 91 ng/ml) in the patients with IBD was lower compared with that in the controls (227 +/- 79 ng/ml, P<0.035). Similarly, the mean IGFBP-3 concentration in the patients was lower than in the controls (1.6 +/- 0.6 ng/ml vs 3.2 +/- 0.7 ng/ml respectively, P<0.001), Serum IL-6 levels were higher in the patients compared with the controls (5.5 +/- 4.2 vs 0.65 +/- 0.11 pg/ml, P<0.0001). The reduced IGF-1 and IGFBP-3 levels in patients with active IBD suggest that this systemic inflammatory condition is associated with a degree of acquired GH resistance, possibly induced by inflammatory cytokines.     

Effect of a high-protein diet on ghrelin, growth hormone, and insulin-like growth factor-I and binding proteins 1 and 3 in subjects with type 2 diabetes mellitus

We have developed a diet that over 5 weeks dramatically lowers plasma glucose in people with type 2 diabetes mellitus. This diet consists of 30% carbohydrate, 30% protein, and 40% fat and is referred to as a Low Biologically Available Glucose (LoBAG) diet. The diet also resulted in an approximately 30% increase in fasting insulin-like growth factor-I (IGF-I). Thus, we were interested in determining if the IGF-I elevation was due to an increase in ghrelin and growth hormone (GH) or to a change in IGF-I binding proteins (IGFBPs). Eight men with type 2 diabetes mellitus ingested a control diet (15% protein, 55% carbohydrate, and 30% fat) and a LoBAG₃₀ diet for 5 weeks in a randomized crossover design with a washout period in between. Before and after each 5-week period, subjects had blood drawn for total glycated hemoglobin and, at several time points over 24 hours, for GH, IGF-I, IGFBP-1, IGFBP-3, ghrelin, glucose, and insulin. Fasting and 24-hour glucose concentrations and total glycated hemoglobin were decreased, as expected (all Ps < .05). Fasting IGF-I increased by approximately 30% (P = .05) and remained unchanged throughout 24 hours. Ghrelin, GH, IGFBP-1, IGFBP-3, and insulin were not different between diets. Insulin and IGFBP-1 concentrations were reciprocal, as expected. Insulin-like growth factor-I binding protein 1 decreased as insulin increased to greater than approximately 30 to 40 μU/mL. Ingestion of a LoBAG₃₀ diet by weight-stable subjects with type 2 diabetes mellitus resulted in an increase in total IGF-I without an increase in ghrelin, GH, and IGFBP-3 or a change in IGFBP-1 regulation. The mechanism remains to be determined.