Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0011854 (type 1 diabetes)
 20,749 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We have determined the level of phosphorylated insulin-like growth factor binding protein-1 (pIGFBP-1) in serum during two catabolic states: diabetes mellitus and trauma. Human sera were incubated with [125I]IGF-I for 2 h followed by non-denaturing PAGE. [125I]IGF-I/IGFBP-1 complexes from serum co-migrated with a pure p4IGFBP-1 standard. Complex formation was specifically inhibited by unlabeled IGF-I. The migration of IGF-I/pIGFBP-1 complexes was retarded by IGFBP-1 antibodies, but not by antibodies against IGFBP-2 or IGFBP-3. Sera from three severely traumatized patients had up to 12-fold more pIGFBP-1 than sera from age-matched controls. The level of pIGFBP-1 was reduced in all three patients upon hospital discharge. Sera from three patients with insulin dependent diabetes mellitus (IDDM) and severe ketoacidosis (DKA) had more pIGFBP-1 than controls. Administration of insulin to DKA patients lowered the level of pIGFBP-1. The present study shows that IGFBP-1 exists as a free, high affinity, phosphorylated form in vivo during two catabolic states.
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PMID:Phosphorylation of insulin-like growth factor binding protein-1 in patients with insulin-dependent diabetes mellitus and severe trauma. 751 91

Type 1 diabetes mellitus is associated with decreased insulin-like growth factor-1 (IGF-1) levels, enhanced values of growth hormone (GH) and IGF-binding protein 1 (IGFBP-1). Since the liver is the major source of IGF and IGFBP production, we have therefore examined whether levels of IGFs (IGF-1 and IGF-11) and IGFBPs (IGFBP-1 and IGFBP-3) differ when insulin is infused into the portal or peripheral vascular system. IGF, IGFBP, and GH levels were determined within 1-3 weeks of diagnosis in 36 patients (ranging in age from 18 to 22 years) with Type 1 diabetes mellitus. IGF-1 levels were low before insulin therapy administration (0.49 +/- 0.05 vs. 1.11 +/- 0.04 U/ml in controls, P < 0.01). With insulin treatment, IGF-1 levels rose to the normal range and IGF-1 normalisation depended on diabetes control and the route of insulin infusion. Diabetic patients with conventional insulin therapy (CIT; n = 12) had low IGF-1 (0.57 +/- 0.07 U/ml) compared with patients with continuous subcutaneous insulin infusion (CSII; n = 12; 0.75 +/- 0.08 U/ml; P < 0.05) and intraportal insulin infusion (IPII; n = 12; 1.07 +/- 10.05 U/ml; P < 0.05). Significant correlations were found between IGF-1 and parameters of glycemic control: HbA1c (r = -0.64; P < 0.01) and glycemia (r = -0.56; P < 0.05). The pattern of changes in IGF-11 levels was not significantly different from that of controls and was not altered by insulin therapy (0.98 +/- 0.08 and 1.01 +/- 0.04 U/ml in controls). Measured fasting 08:00 h IGFBP-1 levels were elevated 3-fold and IGFGP-3 levels were 2-fold lower in diabetic patients than in controls. Elevated IGFBP-1 levels were significantly correlated with metabolic control (glycemia, r = 0.64, P < 0.01; HbA1c, r = 0.71, P < 0.01). The mean elevated GH level before insulin administration (13.4 +/- 0.9 mg/l) was decreased by intensified insulin therapy (CSII, 8.8 +/- 0.6, P < 0.05; IPII, 5.6 +/- 0.9 mg/l, P < 0.001). There was a negative correlation between GH and IGF-1 (r = -0.72, P < 0.01). These results show the role of glycemic control and the route of insulin administration in the normalisation of IGF-1, IGFBP-1 and GH up to non-diabetic controls in patients with recent-onset Type 1 diabetes mellitus.
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PMID:Insulin-like growth factors and binding proteins in patients with recent-onset type 1 (insulin-dependent) diabetes mellitus: influence of diabetes control and intraportal insulin infusion. 753 Jun 21

Growth hormone (GH) secretion disorders have been reported in poorly controlled type I diabetes mellitus patients. Our work was aimed to evaluate GH secretion in 9 type I young diabetes mellitus patients as well as the low molecular weight IGF-binding protein secretion (IGFBP-1) in 5 of them. The patients did not show any signs of malnutrition or neurovascular complications, neither were they on any medication except for insulin. The study protocol included blood samples collection during a 24-h period for measurement of glucose, glycated hemoglobin, GH IGF-I and IGFBP-1 levels under two situations: on poor glycemic control and after 2-3 months on better control through systematic diet, low in carbohydrates and increase in insulin dosage. GH secretion data were analyzed by Cluster algorithm for pulsatility parameters; for rhythm assessment Cosinor method was used. The first study (poor control) reported significant increase of GH maximal and incremental amplitude and duration pulse values, when compared to the second study (better control). Mean 24-h secretion values as well mean GH for interpulse intervals (valleys) decreased, although not statistically significant. The fraction of pulsatile GH/24 h GH did not change significantly with better glycemic control. No changes in pulse frequency were observed. Mean IGF-I concentrations were significantly higher when patients were on better glycemic control. An ultradian variation for GH secretion was noticed in the first study (poor control) and a circadian variation in the second one (better control). IGFBP-1 analysis showed significant decrease of the mean 24-h values under better glycemic control. Linear regression analysis demonstrated a correlation between IGFBP-1 levels and fasting glucose levels. A circadian variation was present in IGFBP-1 secretion, irrespective of glycemic control. Therefore, we concluded that for type I diabetic patients: 1. GH secretion is increased on poor control, through maximal, incremental amplitude and pulse duration values; 2. IGFBP-1 values were significantly reduced and IGF-1 levels significantly higher after better glycemic control; 4. GH ultradian secretion is reported on poor control, and circadian on the better one, 5. IGFBP-1 circadian secretion occurred irrespective of glycemic control.
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PMID:Effect of glycemic control on growth hormone and IGFBP-1 secretion in patients with type I diabetes mellitus. 888 37

Pubertal development has recently been evaluated from the standpoint of changes in insulin-like growth factor (IGF)-I and IGF-binding protein-3 (IGFBP-3) levels in healthy children. We studied puberty related changes in serum IGF-I and IGFBP-3 levels in 24 patients (11 prepubertal) with insulin dependent diabetes mellitus (IDDM) and 26 healthy subjects (14 prepubertal). Serum IGF-I and IGFBP-3 levels were assayed using immunoradiometric assays and radioimmunoassays, respectively. Serum IGF-I and IGFBP-3 levels in diabetics did not increase during puberty, as opposed to those in healthy children. Serum IGF-I and IGFBP-3 levels of diabetic patients were found to be lower than those of control subjects during puberty (p < 0.0001 and p < 0.05, respectively). Proteolysis is believed to be a general mechanism to increase IGF bioavailability in the presence of IGFBPs. Increased IGFBP-3 protease activity has been shown in sera of children with IDDM as well as a decrease in this activity in response to insulin therapy. Our data displaying low IGFBP-3 levels in diabetic children may be due to increased proteolysis, which also causes a shift in IGF-I to its lower molecular weight forms. Higher rate of clearance of the latter may be the reason for the low IGF-I levels we observed in children with IDDM. The moderate correlation between insulin dose and IGFBP-3 levels (r = 0.5, p < 0.01) may suggest insulin to be a contributing factor in the regulation of IGFBP-3 levels. We conclude that regulation of IGF-I and IGFBP-3 concentrations is disturbed in children with IDDM, in particular during adolescence.
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PMID:Serum levels of insulin-like growth factor-I and insulin-like growth factor binding protein-3 in children with insulin-dependent diabetes mellitus. 891 Aug 17

In type 1 diabetes mellitus (DM 1), high GH basal levels and exaggerated GH responses to several stimuli, including GHRH, have been described. GH-releasing peptide-6 (GHRP-6) is a synthetic hexapeptide that specifically stimulates GH release, both in vitro and in vivo. The aim of this study was to evaluate the effects of GHRP-6 alone or in combination with GHRH on GH secretion in DM 1. Six type 1 diabetic males and six age-, sex-, and body mass index-matched control volunteers were studied. Each subject received GHRH (100 microg iv), GHRP-6 (90 microg iv), and GHRH plus GHRP-6 on three separate days. GH peak values were higher in DM 1 patients than in control volunteers, after GHRH (52.2+/-9.8 vs. 19.3+/-6.0 microg/L; P = 0.016), GHRP-6 (66.2+/-9.6 vs. 39.9+/-6.3 microg/L; P = 0.05), and GHRH plus GHRP-6 (81.8+/-4.4 vs. 53.7+/-8.2 microg/L; P = 0.01). An additive GH response to combined administration of these two peptides was observed in diabetic patients. Serum insulin-like growth factor (IGF)-1 levels were diminished in DM 1, with respect to normal subjects (145.2+/-21.5 vs. 269.7+/-42.0 microg/L; P = 0.01), whereas IGF-binding protein-3 levels were not significantly different between DM-1 and controls. In summary, GHRP-6 is a potent stimulus for GH secretion in DM 1. The combined administration of GHRP-6 plus GHRH constitutes the most powerful stimulus for GH secretion in DM 1. These patients exhibit a greater GH secretory capacity than normal subjects, probably caused by a diminished tone in the IGF-1 sustained negative feedback control exerted upon somatotroph responsiveness.
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PMID:Growth hormone (GH) response to GH-releasing peptide-6 in type 1 diabetic patients with exaggerated GH-releasing hormone-stimulated GH secretion. 976 81

Type 1 diabetes mellitus (DM) is a disease of insulin deficiency, resulting from the autoimmune-mediated destruction of pancreatic beta cells. However, as a likely consequence of intraportal insulin deficiency, patients with type 1 DM also exhibit abnormalities of the growth hormone (GH)/IGF/IGF-binding protein (IGFBP) axis, including GH hypersecretion, reduced circulating levels of insulin-like growth factor-I (IGF-I) and IGFBP-3, and elevated levels of IGFBP-1. These abnormalities not only exacerbate hyperglycemia in patients with type 1 DM, but may contribute to the pathogenesis of diabetes-specific complications, including diabetic neuropathy, nephropathy, and retinopathy. Therefore, therapeutic modalities aimed at restoring the GH-IGF-IGFBP axis are being considered. Herein, we review the efficacy of one such therapy, specifically IGF-I replacement therapy. To date, short-term beneficial metabolic effects of recombinant human IGF (rhIGF)-I therapy have been demonstrated in numerous diabetic conditions, including type 1 DM, type 2 DM, and type A insulin resistance. However, the long- term safety and metabolic efficacy of rhIGF-I therapy remains to be established. Moreover, the potential impact of rhIGF-I on the natural history of diabetic complications has yet to be explored.
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PMID:Insulin-like growth factor-I in diabetes mellitus: its physiology, metabolic effects, and potential clinical utility. 1146 25

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.
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PMID:The role of IGF-binding proteins in mediating the effects of recombinant human IGF-I on insulin requirements in type 1 diabetes mellitus. 1150 96

Correlation studies have suggested that IGF-binding protein (IGFBP)-1 is a dynamic regulator of free IGF-I. To further study this, we developed a monoclonal immunofluorometric assay specific for the binary complex of IGF-I and IGFBP-1 in human serum. An IGFBP-1 antibody, which recognizes all phospho-forms of IGFBP-1, was used for coating. An europium-labeled IGF-I antibody served as tracer. Assay incubation was performed at conditions approaching those in vivo (i.e. pH 7.4, 37 C). The assay was highly specific: no signal was obtained unless both IGF-I and IGFBP-1 were present and neither IGFBP-2, -3, -4, nor IGF-II caused any cross-reaction. The linear standard curve covered 3 orders of magnitude, and within and in-between assay coefficients of variation were less than 5 and 15%, respectively. To study the dynamic relationship between free IGF-I and binary complex formation, seven healthy subjects were fasted for 72 h. Samples were collected every 3 h. During fasting, free IGF-I was reduced by two thirds (P < 0.0001). IGFBP-1 and the binary complex increased in parallel (P < 0.0001), and levels correlated positively in all subjects (0.89 < or = r < or = 0.98; P < 0.0001). Free IGF-I correlated inversely with IGFBP-1 (-0.81 < or = r < or = -0.48; 0.0001 < or = P < or = 0.05) and the binary complex (-0.79 < or = r < or = -0.41; 0.0001 < or = P < or = 0.05). To study overnight fasting levels, we compared healthy controls and patients with type 1 diabetes and chronic renal failure (n = 10), because these patients show profound alterations in their IGF-system. In both groups, the binary complex was increased about 2.5-fold (P < 0.0001), whereas IGFBP-1 was increased by 5- to 6-fold (P < 0.0001). Accordingly, free IGF-I was severely reduced (P < 0.0001). In conclusion, the assay enables us to study the role of IGFBP-1 as a dynamic regulator of free IGF-I. Our results clearly show that IGFBP-1 and free IGF-I are tightly associated peptides. Furthermore, it has now become possible to compare levels of IGF-I carried within the binary complex IGFBP-1:IGF-I in different (patho-) physiological conditions.
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PMID:Development and clinical evaluation of a novel immunoassay for the binary complex of IGF-I and IGF-binding protein-1 in human serum. 1178 56

It was recently discovered that the streptozotocin (STZ)-diabetic mouse model is characterised by GH hypersecretion in contrast to the STZ-diabetic rat, the former thus mimicking the changes in GH in human type 1 diabetes. Inhibition of circulating and renal IGF-I by long-acting somatostatin analogues reduces renal and glomerular growth and urinary albumin excretion in diabetic rats. The aim of the present study was to examine renal and glomerular growth in early experimental diabetes in mice along with changes in the GH/IGF-I axis following treatment with the somatostatin analogue octreotide. Balb/C(a) mice were randomised into non-diabetic controls, placebo-treated and octreotide-treated diabetic (50 microg/day) mice and examined 7 and 14 days after induction of diabetes. There was no effect of octreotide treatment on body weight, glycaemic control or food intake. However, octreotide treatment significantly inhibited renal and glomerular growth by the end of the study period when compared with placebo treatment. In addition, octreotide prevented an increase in kidney IGF-I by day 7. GH hypersecretion was observed in the diabetic groups but octreotide treatment reduced GH levels compared with placebo treatment by day 14. No significant differences in serum or kidney IGF-binding protein-3 levels were observed between placebo- and octreotide-treated diabetic mice. In conclusion, this new diabetic mouse model mimicking human type 1 diabetes is characterised by GH hypersecretion and the somatostatin analogue octreotide is able to prevent renal and glomerular growth, probably mediated through changes in circulating GH and local kidney IGF-I levels.
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PMID:Inhibitory effects of octreotide on renal and glomerular growth in early experimental diabetes in mice. 1187 12

Disturbances in the relations between insulin, growth hormone (GH) and insulin-like growth factor I (IGF-I) may be a major cause behind deteriorated metabolic control in adolescent girls with type I diabetes. These patients have increased GH secretion and low IGF-I concentrations. The aim of this study was to identify possible endocrine mechanisms behind good and poor glycaemic control in such girls, focusing on the insulin-GH-IGF-I axis. Ten girls with well-controlled insulin-dependent diabetes mellitus (IDDM), hemoglobin A1c (HbA1c) 6.5+/-0.4% (normal range 3.9-5.2%) and nine healthy controls were investigated and compared with 11 girls with poor glucose regulation, HbA1c 10.9+/-0.4%, and their corresponding controls. Serum profiles of glucose, insulin, GH and IGF-binding protein 1 (IGFBP1) were analysed in addition to IGF-I and HbA1c. Two interesting observations were made. GH concentrations were equally elevated in the two diabetic groups regardless of metabolic control (mean 24 h GH - girls with poorly controlled diabetes 10.0+/-1.0 mU/L vs 9.8+/-1.7 - girls with well-controlled diabetes; p=ns). Likewise, the IGF-I concentrations were reduced to the same extent (233+/-19 vs 242+/-23 microg/L; p=0.75). Secondly, despite similar insulin concentrations (mean 24 h insulin - girls with poorly controlled diabetes 22.9+/-2.6 and girls with well-controlled diabetes 27.3+/-2.9 mU/L, respectively; p=0.26), there was a marked difference in IGFBP1 concentrations between the two groups with IDDM (mean IGFBP1 - girls with poorly controlled diabetes 70.5+/-9.1 microg/L vs girls with well-controlled diabetes 28.6+/-3.3; p<0.001). Despite equally elevated GH concentrations that may induce insulin resistance, the markedly lower concentrations of IGFBP1 in the well-controlled group indicate a higher hepatic insulin sensitivity in these girls compared with those with a poor control. Furthermore, in spite of similar total IGF-I concentrations, the lower IGFBP1 concentrations may result in higher IGF-I bioactivity in the well-controlled group. This may be reflected in better growth of the well-controlled group whose height of 168.7+/-0.9 vs 163.6+/-1.2 cm was significantly different (p<0.004). IGFBP1 may be a marker of overall insulinization in adolescents with type 1 diabetes, independent of the absolute insulin dose used for therapy.
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PMID:Profound changes in the GH-IGF-I system in adolescent girls with IDDM: can IGFBP1 be used to reflect overall glucose regulation? 1501 22


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