Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0011849 (diabetes)
 277,896 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Values of IGF-I after extraction, its binding proteins, and the high affinity GH-binding protein (BP) are not well established in pediatric patients with insulin-dependent diabetes mellitus (IDDM). We report data for IGF-I, IGFBP-1, and -3, and GHBP in 92 Spanish children with IDDM, separated according to pubertal stage: prepubertal (n = 49); pubertal onset (n = 17); mid-puberty (n = 17), and complete puberty (n = 9), as well as to metabolic control (HbA1 < 9% or > or = 9%). IGF-I levels in IDDM patients increased throughout development (p < 0.001), but were diminished at every developmental stage when compared with marched control subjects. IGF-I concentrations showed a negative correlation with the degree of metabolic control, in particular during the prepubertal stage of development. A negative correlation (r = -0.22; p < 0.005) between IGF-I concentrations and HbA1 was found. Serum IGFBP-I levels diminish during maturation in diabetic patients (p < 0.001). However, IDDM patients have significantly higher levels of IGFBP-1 than control subjects at every stage of development, and IDDM patients with inadequate metabolic control exhibit even greater differences when compared with matched control subjects. A positive correlation (r = 0.22; p < 0.005) between IGFBP-1 concentrations and HbA1 was found. IGFBP-3 serum levels were similar to those observed in normal subjects, and no correlation was observed in relation to the metabolic control. In IDDM patients, GHBP levels change significantly during maturation, as they do in normal control subjects; however, significantly lower GHBP levels were found in prepubertal and pubertal IDDM patients. GHBP levels were independent of metabolic control, although a tendency toward lower levels of GHBP was seen when HbA1 levels increased. We suggest that a partial GH resistance syndrome exists in IDDM patients, and this may be related to the metabolic control. Hence, the biochemical markers measured here may be of value in evaluating the smaller pubertal growth spurt in diabetic patients.
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PMID:Insulin-like growth factor I, its binding proteins 1 and 3, and growth hormone-binding protein in children and adolescents with insulin-dependent diabetes mellitus: clinical implications. 872 60

In Type 1 diabetes, high circulating growth hormone (GH) in conjunction with low plasma insulin-like growth factor-I (IGF-I) is indicative of a hepatic GH-resistance profile since the liver is the main source of circulating IGF-I. The reduction in specific growth hormone binding protein (GHBP), corresponding to the extracellular domain of the GH receptor, provides an indirect indication of the hepatic density of GH receptors, as does the reduction in IGFBP-3, the major IGF binding protein, which is GH-dependent. Type 1 diabetes is also associated with high levels of IGFBP-1, a binding protein down-regulated by insulin. Although most of these abnormalities have been described in situations of poor glycaemic control, hyperglycaemia does not seem to be the predominant factor in their pathogenesis. Even intensified subcutaneous insulin therapy does not normalize GH, IGF-I, GHBP and IGFBP-3 plasma levels. Some indirect evidence suggests that portal insulinopenia plays a role in the hepatic GH-resistance profile of Type 1 diabetes, i.e. discrepancies between the abnormalities reported in Type 1 and Type 2 diabetes, and the inverse relationship between residual insulin secretion in Type 1 diabetes and some of these abnormalities. Intraperitoneal insulin therapy administered to Type 1 diabetic patients by implantable pumps (without modification of glycaemic control) can improve GHBP activity, practically normalize plasma IGF-I and normalize IGFBP-3. The improvement in GH-IGF-I axis disorders obtained with intraperitoneal insulin therapy (which allows primary portal insulin absorption) provides direct evidence of the central role of portal insulin in the regulation of this system.
Diabetes Metab 1996 Jul
PMID:Insulin therapy and GH-IGF-I axis disorders in diabetes: impact of glycaemic control and hepatic insulinization. 876 70

Growth hormone (GH) insensitivity is a pathological state characterized by a disturbance of the physiological relationship between GH secretion, synthesis of insulin-like growth-factor I (IGF-1) and the biological actions of GH. Laron syndrome, the prototype for GH insensitivity, is most often due to GH receptor deficiency. However, this syndrome is heterogeneous in terms of growth characteristics, bio-chemical features and, most importantly, genetic defects. Recent data have indicated that partial GH receptor deficiency could be involved in children with apparently idiopathic short stature. Laron syndrome, because of extreme growth deficiency and a lack of alternative treatment, was the first clinical situation in which recombinant human IGF-1 was used. IGF-1 accelerates growth rate in most patients, induces subtle modifications of the craniofacies and decreases fat mass. However, it is still too early to evaluate the long-term effects of IGF-1 on final height. Tolerance to the drug has been excellent in all reported trials. The major (but rare) side effects are transient intracranial hypertension and hypokalemia. Generalization of data obtained in Laron syndrome to other clinical situations should take account of the profound alterations in IGF-1 pharmacokinetics resulting from a deficiency in IGF-binding proteins.
Diabetes Metab 1996 Jul
PMID:Growth hormone insensitivity syndrome (Laron syndrome): main characteristics and effects of IGF1 treatment. 876 71

Growth hormone (GH) hypersecretion and relative insulin-like growth factor I (IGF-I) deficiency have been implicated in the development of insulin resistance, poor metabolic control, and impaired growth during puberty in insulin-dependent diabetes mellitus (IDDM). Portal levels of insulin are critical for the integrity of the hepatic GH receptor and suppression of the inhibitory IGF-binding protein I. Increasing insulin doses during puberty will result in adequate portal levels of insulin and thus restore IGF-I levels and IGF bioactivity, but at the risk of nocturnal hypoglycaemia and weight gain. Restoration of normal circulating levels of IGF-I using the recombinant peptide will lead to reductions in GH levels and improved insulin sensitivity. Given as a daily subcutaneous injection, low-dose recombinant human IGF-I (40 micrograms/kg/day) could prove to be a useful adjunct to standard insulin therapy during puberty in IDDM. The reduced and more stable insulin requirement might reduce the risks of nocturnal hypoglycaemia and weight gain. However, whereas intensified insulin therapy will reduce the risk of microangiopathic complications, the benefits of combination therapy have not been proven. The role of recombinant human IGF-I in the treatment of IDDM needs to be tested by long-term controlled trials.
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PMID:Growth hormone insulin-like growth factor I axis in insulin-dependent diabetes mellitus. 885 34

Obesity, short stature, decreased growth rate and delayed skeletal maturation are common features of children with Prader-Willi syndrome (PWS). In contrast to PWS, children with simple exogenous obesity have normal or increased growth rate and normal or advanced skeletal maturation. Decreased growth hormone (GH) secretion evaluated by pharmacological or physiological testing associated with increased plasma insulin-like growth factor (IGF-I) and GH-binding protein (GH-BP) levels are also characteristic of simple obesity. In order to understand whether the suboptimal GH secretion in PWS is an artifact of the obesity, we studied 33 obese and 11 non-obese PWS children, aged 2-16 years.GH secretion was evaluated with three pharmacological stimuli (insulin, clonidine and L-dopa) and by spontaneous 24-hour GH secretion. Skeletal maturation was delayed in 70% whereas plasma IGF-I and GH-BP were either low or normal. Forty subjects, including ten non-obese children, had GH deficiency by standard testing (failure to respond to two pharmacological stimuli), and all but one had blunted spontaneous 24-h GH secretion. No significant correlation between body mass index (wt/ht2) and spontaneous 24-h GH secretion (r = 0.145), p > 0.06) or GH-BP levels (r = 0.19, p > 0.07) was found. Thirty documented GH deficient children have completed at least two years of GH therapy. With treatment the overall mean height SD and weight SD changed from -2.2 to -0.8 and from 3.5 to 2.4 respectively (p < 0.0001). No patient has developed diabetes mellitus. In conclusion, growth velocity, skeletal maturation, GH secretion and GH dependent proteins in PWS resemble GH deficiency more than simple obesity. Our ongoing study suggests that GH deficiency in PWS is not an artifact of obesity. Although it is unlikely that GH deficiency is the only cause of decreased growth velocity and increased adiposity in PWS, it is a common feature and significant contributory factor. Long term observation will be required until achievement of adult height to determine whether GH therapy actually improves final height.
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PMID:Growth hormone secretion and effects of growth hormone therapy on growth velocity and weight gain in children with Prader-Willi syndrome. 888 49

Low plasma insulin-like growth factor (IGF)-I despite high circulating growth hormone (GH) in insulin-dependent diabetes mellitus (IDDM) indicate a hepatic GH resistance. This state may be reflected by the reduction of the circulating GH binding protein (GHBP), corresponding to the extracellular domain of the GH receptor, and the reduction of insulin-like growth factor binding protein (IGFBP)-3, major IGF-I binding protein, upregulated by GH. We carried out two studies. In the first, plasma GHBP activity was compared in patients with IDDM on continuous subcutaneous insulin infusion (CSII) or on conventional therapy and in healthy subjects. In the second study, the 18 patients on CSII at baseline were then treated by continuous intraperitoneal insulin infusion with an implantable pump (CPII) and prospectively studied for GH-IGF-I axis. Although HbA1c was lower in patients on CSII than in those on conventional therapy, GHBP was similarly reduced in both when compared to control subjects (10.2 +/- 0.8 and 11.6 +/- 0.9% vs 21.0 +/- 1.3, p < 0.01). CPII for 12 months resulted in: a slight and transient improvement in HbA1c (Time (T)0: 7.6 +/- 0.2%, T3: 7.1 +/- 0.2%, T12: 7.5 +/- 0.2%, p < 0.02), improvement in GHBP (T0: 10.2 +/- 0.8%, T12: 15.5 +/- 1.5, p < 0.0001), near-normalization of IGF-I (T0: 89.4 +/- 8.8 ng/ml, T12: 146.9 +/- 15.6, p < 0.002) and normalization of IGFBP-3 (T0: 1974 +/- 121 ng/ml, T12: 3534 +/- 305, p < 0.0001). The hepatic GH resistance profile in IDDM does not seem to be related to glycaemic control, but partly to insufficient portal insulinization. Intraperitoneal insulin delivery, allowing primary portal venous absorption, may influence GH sensitivity, and improve hepatic IGF-I and IGFBP-3 generation.
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PMID:Effect of intraperitoneal insulin delivery on growth hormone binding protein, insulin-like growth factor (IGF)-I, and IGF-binding protein-3 in IDDM. 896 Aug 32

Elevated GH levels are frequently seen in poorly controlled type I diabetics and have been implicated in diabetic complications. Studies of GH and GH antagonist (GHA) transgenic mice with streptozotocin (STZ)-induced diabetes have revealed that GH has a permissive effect for diabetic nephropathy, and that expression of a GHA gene protected mice against diabetic kidney lesions. To investigate whether kidney GH receptor (GHR) and/or GH-binding protein may play a role in diabetic nephropathy, we evaluated GH-specific binding and messenger RNA levels for GHR/GH-binding protein in mouse livers and kidneys from bovine (b) GH or bGHA transgenic (Tg) mice and their nontransgenic (NTg) littermates with or without STZ-induced diabetes. We found that liver-specific GH binding is significantly higher in both bGH- and bGHA-Tg mice compared to that in their NTg controls. In contrast, kidney GH binding is significantly lower in bGH-Tg mice compared to that in NTg littermates. These results indicate that regulation of mouse GHR expression is tissue specific. STZ-induced diabetes decreased GH-specific binding in both liver and kidney of NTg and GHA-Tg mice, but not in bGH-Tg mice. The lowered GHR binding in diabetic NTg and GHA-Tg mice suggests the involvement of insulin in the regulation of GHR expression. The down-regulation of kidney GHR in GHA-Tg mice in combination with the presence of GHA may partially explain the protective mechanism of GHA against diabetic kidney lesions.
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PMID:Liver and kidney growth hormone (GH) receptors are regulated differently in diabetic GH and GH antagonist transgenic mice. 911 97

To date, measurements of GH-binding protein (GHBP) during human pregnancy have been carried out using assays susceptible to interference by the elevated levels of human placental GH typical of late gestation. We recruited a large cohort of pregnant women (n = 140) for serial measurements of GHBP and used the ligand immunofunctional assay for GHBP. For normal gravidas, GHBP levels fell throughout gestation. Mean levels were 1.07 nmol/L (SE = 0.18) in the first trimester, 0.90 nmol/L (SE = 0.08) at 18-20 weeks, 0.73 nmol/L (SE = 0.05) at 28-30 weeks, and 0.62 nmol/L (SE = 0.06) at 36-38 weeks. GHBP levels in the first trimester correlated significantly with maternal body mass index (r = 0.58; P < 0.01). GHBP levels in pregnancies complicated by noninsulin-dependent diabetes mellitus (NIDDM) were substantially elevated at all gestational ages. The mean value in the first quarter (2.29 nmol/L) was more than double the normal mean (P < 0.01). In contrast, patients with insulin-dependent diabetes mellitus (IDDM) showed reduced GHBP concentrations at 36-38 weeks. The correlation between body mass index and GHBP is consistent with a metabolic role for GHBP during pregnancy, as is the dramatic elevation in GHBP observed in cases of NIDDM. At 36 weeks gestation, GHBP was significantly elevated (P < 0.01) in those women whose neonates had low birth weight (< 10th percentile). In early gestation (< 14 weeks), GHBP tended to be higher in women whose fetuses were designated to be at risk of intrauterine growth retardation (1.39 nmol/L; n = 4; compared with 1.07 nmol/L in normals), but this did not reach statistical significance. Although both NIDDM and IDDM pregnancies are at risk of fetal macrosomia, their GHBP concentrations are markedly divergent. This paradox and the roles of glucose and insulin in the regulation of GHBP during gestation warrant further investigation.
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PMID:Growth hormone-binding protein in normal and pathologic gestation: correlations with maternal diabetes and fetal growth. 917

Pituitary growth hormone (GH) is essential for postnatal growth in animals. GH exerts its actions by direct effect on target organs and by stimulating the production of insulin-like growth factor I (IGF-I). At the tissue level, the pleiotropic actions of GH result from the interaction of GH with a specific cell surface receptor, the GH receptor (GHR). The GHR belongs to the hematopoietic receptor superfamily. The human GHR is the product of a single gene located on chromosome 5p13.1-p12 and spans at least 87 kb. Transcripts from this gene are characterized by the presence of disparate 5' untranslated exons. In the liver at least eight different GHR 5' untranslated regions (UTRs) have been described. This heterogeneity in the 5' UTR most likely results from the splicing of the various exon 1 fragments to a common splice site located 11 bp upstream of the initiating ATG. Heterogeneity in the 5' UTR sequences of the GHR transcripts indicates that transcriptional control of the locus is complex. GHR gene expression is minimal to absent in the fetus, with the postnatal increase in expression in the liver being maximal during pregnancy. GHR gene expression is also regulated by factors such as nutritional intake, GH, steroid hormones, and diabetes mellitus. Available information about the molecular mechanisms regulating expression of the GHR gene is discussed. Thus the GHR gene presents a picture of multiple 5' untranslated exons under the control of multiple promoters. The use of alternate promoters for initiation of transcription in conjunction with differential splicing allows for exquisite regulation of gene expression. This schema is appropriate for a protein that is essential to many of the physiological processes that are crucial for the survival and well-being of the organism.
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PMID:Regulation of growth hormone receptor gene expression. 963 92

Formation of new beta cells can take place by two pathways: replication of already differentiated beta cells or neogenesis from putative islet stem cells. Under physiological conditions both processes are most pronounced during the fetal and neonatal development of the pancreas. In adulthood little increase in the beta cell number seems to occur. In pregnancy, however, a marked hyperplasia of the beta cells is observed both in rodents and man. Increased mitotic activity has been seen both in vivo and in vitro in islets exposed to placental lactogen (PL), prolactin (PRL) and growth hormone (GH). Receptors for both GH and PRL are expressed in islet cells and are upregulated during pregnancy. By mutational analysis we have identified different functional domains of the cytoplasmic part of the GH receptor. Thus the mitotic signaling only requires the membrane proximal part of the receptor and activation of the tyrosine kinase JAK2 and the transcription factors STAT1 and 3. The activation of the insulin gene however also requires the distal part of the receptor and activation of calcium uptake and STAT5. In order to identify putative autocrine growth factors or targets for growth factors we have cloned a novel GH/PRL stimulated rat islet gene product, Pref-1 (preadipocyte factor-1). This protein contains six EGF-like motifs and may play a role both in embryonic pancreas differentiation and in beta cell growth and function. In summary, the increasing knowledge about the mechanisms involved in beta cell differentiation and proliferation may lead to new ways of forming beta cells for treatment of diabetes in man.
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PMID:Beta cell proliferation and growth factors. 993 Sep 29


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