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Query: UMLS:C0011849 (diabetes)
 277,896 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Growth hormone (GH) plays an important role in glucose homeostasis in both healthy subjects and patients with diabetes. Patients with poorly controlled insulin-dependent diabetes mellitus (IDDM) have high basal and integrated serum GH concentrations, as well as an enhanced GH response to several secretagogues. Yet, these patients have impaired generation of insulin-like growth factor-I (IGF-I). These abnormalities tend to return to normal as an adequate metabolic control is achieved. In view of this hormonal profile, IDDM has been considered a state of relative GH resistance. Studies in experimental animals with streptozotocin-induced diabetes have shown a decreased binding of radiolabeled GH to liver membranes. More recently, adults and children with IDDM have been found to have low levels of the high affinity growth hormone binding protein (GHBP), which represents the extracellular portion of the GH receptor, and is thought to reflect GH receptor tissue concentrations. The abnormalities in the GH/IGF-I axis have been implicated in the worsening of metabolic control that occurs in some patients, as well as in the development of microvascular complications, particularly retinopathy.
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PMID:Characteristics of the somatotropic axis in insulin dependent diabetes mellitus. 762 Feb 73

Recent advances in the understanding of circulating growth hormone binding proteins (GHBP) are reviewed. The high affinity GHBP represents the ectodomain of the GH receptor (GHR); it is either cleaved from membrane-bound GHRs (man, rabbit) or derived from an alternatively spliced GHR mRNA (rodents). Another circulating GHBP, of low affinity and not GHR-related, is only partially characterized. The GHBPs complex about half of the GH in human plasma. They act as a buffer regulating free and bound GH, prolong GH half-life, and modulate GH bioactivity through competition with GHRs for ligand. The plasma levels of both GHBPs are developmentally upregulated during childhood and remain relatively constant thereafter. Different species vary in their regulation of GHBP, with sexual dimorphism and large pregnancy-related changes in some but not all species. A variety of conditions associated with altered GH responsivity (resistance or hypersensitivity) are attended by altered levels of the high affinity GHBP. Generally, GH resistance is characterized by decreased GHBP levels, and the converse is true in GH hypersensitivity such as in obesity. It has been postulated that the plasma GHBP level reflects tissue concentrations of the GHR, but this remains to be proven. The high affinity GHBP appears to be positively, though imperfectly, linked to GH action. Soluble receptor isoforms analogous to the GHBP have been demonstrated for several members of the cytokine receptor family to which the GHR belongs. The ultimate biological role of these circulating receptor ectodomains remains to be fully defined.
Exp Clin Endocrinol Diabetes 1995
PMID:Growth hormone binding to a circulating receptor fragment--the concept of receptor shedding and receptor splicing. 762 Nov

A specific radioimmunoassay for human IGFBP-2 was developed using a polyclonal antiserum directed against a partial sequence (hIGFBP-2(176-190)). The tracer was prepared by radioiodination of a [Tyr]o-hIGFBP-2(176-190) derivative. The assay was used to study IGFBP-2 levels in numerous clinical and experimental situations. There was little circadian fluctuations of serum level which showed a marked age-dependence with high levels at birth and senescence and low levels during puberty. Decreased IGFBP-2 levels were present in untreated insulin-dependent diabetes mellitus (IDDM), in acromegaly and during dexamethasone suppression test. GH deficiency, fasting, IGF-I administration to patients with GH receptor deficiency, hepatic failure and insulinomas caused a moderate increase of serum IGFBP-2. Markedly elevated levels were found in chronic renal failure, non-islet cell tumour induced hypoglycemia and leukaemias. The fact that all possible relationships between insulin secretion and IGFBP-2 levels could be identified suggests that insulin is not a major regulator. In general, there was an inverse relationship with serum IGFBP-3 (except IDDM) and IGFBP-2 levels were high in situations where free IGF-II should be expected to be high. The tentative conclusion would therefore be that free IGF-II is a major regulator of circulating IGFBP-2.
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PMID:Clinical studies of IGFBP-2 by radioimmunoassay. 768 12

To investigate GH's role in diabetic end organ damage, experimental diabetes was induced with streptozotocin (STZ) in bovine GH (bGH) or bGH antagonist transgenic mice and in their nontransgenic (NTG) litter mates. Body growth, blood glucose, serum insulin-like growth factor-I levels, liver GH receptor (GHR) binding, and kidney histology of these animals were evaluated. After administration of multiple low doses of STZ, 90% of the mice developed hyperglycemia. The diabetic animals, especially those expressing GH and GH antagonist transgenes, demonstrated retarded body growth and reduced insulin-like growth factor-I levels when compared with their nondiabetic litter mates. Kidney histology revealed severe glomerulosclerosis in diabetic and nondiabetic bGH transgenic mice. Diabetic NTG mice exhibited moderate kidney lesions. Diabetic bGH antagonist transgenic mice possessed normal glomeruli indistinguishable from those seen in nondiabetic NTG mice. GHR-binding assays revealed that liver GHR-binding sites were significantly reduced in diabetic NTG mice and transgenic dwarf mice when compared with their nondiabetic controls. Conversely, liver GHR-binding ability was significantly increased in bGH transgenic mice as compared with their NTG littermates and remained high during diabetes. It is concluded that transgenic mice that express a GH antagonist are protected from diabetes and or GH-induced nephropathy.
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PMID:Effects of streptozotocin treatment in growth hormone (GH) and GH antagonist transgenic mice. 783

Abnormalities of GH secretion and clearance are well-documented in poorly controlled insulin-dependent diabetes mellitus (IDDM), but the contribution of the receptor (GHR) and the GH-binding protein (GHBP) to these abnormalities has not been defined. We studied the expression of the GHR/GHBP gene in the livers, hearts and kidneys in streptozocin-induced diabetes (STZ-D) in the rat. GHR and GHBP mRNA levels were measured by Northern blot and ribonuclease protection assays. Whereas levels of GHR and GHBP mRNA were significantly decreased in liver and heart of STZ-D rats when compared with the control group (P < 0.01), GHR mRNA was significantly increased in the kidneys of STZ-D rats (P = 0.03). Six days of insulin treatment did not significantly alter the levels of GHR/GHBP mRNA in the liver or heart of STZ-D rats, but significantly decreased GHBP mRNA (P = 0.04) in the kidney. Circulating IGF-I was reduced, as was IGF-I mRNA in the liver and heart of STZ-D rats; only circulating IGF-I was restored by insulin treatment. Neither STZ-D nor insulin treatment affected IGF-I or IGF-I receptor mRNA concentrations in the kidney. We conclude that (1) STZ-D modulates the expression of the GHR/GHBP gene and (2) that these changes in GHR/GHBP mRNA concentrations are tissue-specific; STZ-D decreases GHR/GHBP mRNA in liver and heart tissue but increases GHR mRNA concentrations in the kidney. Our results indicate a role for decreased numbers of hepatic GHRs in the pathogenesis of resistance to GH's actions in terms of IGF-I generation and promotion of linear growth in IDDM. We postulate that increased GHR expression in the kidney may be involved in the renal complications of IDDM.
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PMID:Tissue-specific regulation of the growth hormone receptor gene in streptozocin-induced diabetes in the rat. 796 96

Inadequate blood sugar control in children with insulin-dependent diabetes mellitus (IDDM) sometimes results in low insulin-like growth factor-I (IGF-I) and sluggish height growth. High affinity growth hormone-binding protein (GHBP), which is identical to the extracellular domain of growth hormone (GH) receptor, is present in the human sera. We have determined GHBP activity in two cases of poorly controlled IDDM with low height velocity in relation to metabolic control in order to determine the mechanism of resistance to GH in this condition, as indicated by low levels of GH-dependent growth factor IGF-I in the face of high serum GH levels. GHBP activity was within the normal range in two cases of IDDM with slow height velocity, low IGF-I and high hemoglobin-A1. In both cases, improved blood sugar control normalized IGF-I to result in accelerated height velocity without a major change in GHBP levels. These results may indicate either normal peripheral GH receptor or normal free portion of serum GH, and may suggest that the major defect in slow growth in poorly controlled diabetes is due to the post GH receptor.
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PMID:Two cases of insulin-dependent diabetes mellitus under insulin treatment with slow height velocity: relationship of growth hormone-binding protein, metabolic control and growth. 809 76

This study was undertaken (1) to evaluate growth hormone binding protein (GHBP) levels in newly diagnosed patients with Type 1 diabetes before and after insulin therapy and (2) to determine the relationship of GHBP to glycaemic control, C-peptide level and blood pH. GHBP, expressed as a percentage of (125I)GH bound, was determined in 33 patients with Type 1 diabetes (M/F = 19/14, 12.3 +/- 0.4 years) before (day 0), after 5 days (day 5) and after 3 months (month 3) of insulin therapy. At day 0, GHBP was lower in Type 1 diabetes compared with 38 matched healthy control subjects (3.9 +/- 0.4 vs 8.2 +/- 0.4%, p < 0.001). There was no significant improvement in GHBP at day 5 (4.4 +/- 0.3%). At month 3, GHBP increased to (6.0 +/- 0.4%, p < 0.001 vs day 0), but was still lower than controls, p < 0.001. At day 0 GHBP correlated with BMI (r = 0.50, p = 0.001), blood glucose (r = -0.43 p = 0.006) and pH (r = 0.48, p = 0.004), but not HbA1. GHBP at month 3 correlated with day 0 C-peptide (r = 0.41, p = 0.02). Thus, (1) circulating GHBP is low in newly diagnosed patients with Type 1 diabetes, and increases after 3 months of insulin therapy but does not normalize and (2) the severity of biochemical derangement and residual beta-cell function at diagnosis may determine GHBP status and its recovery. We conclude that insulin is an important modulator of GH binding protein in newly diagnosed children with Type 1 diabetes.
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PMID:Insulin therapy increases low plasma growth hormone binding protein in children with new-onset type 1 diabetes. 828 28

Despite elevated serum concentrations of GH, longitudinal growth is stunted in a considerable number of children and adolescents with insulin-dependent diabetes mellitus (IDDM). To elucidate, whether reduced peripheral action of GH contributes to this phenomenon, GH-binding protein (GH-BP) activity was measured in 117 children and adolescents with IDDM (mean age 14.6 yr, range 4.5-28 yr) and 132 healthy controls (13.1 yr, 6.3-26 yr). Serum was incubated with 125I-GH, then chromatographed on a Sephacryl S200 column (1.8.100 cm), apparent binding of 125I-GH to GH-BP was corrected for the amount of endogenous GH present in the sample. GH-BP activity was significantly lower in IDDM patients, with a corrected binding of 16.8 +/- 0.6% compared to 21.3 +/- 0.7% in control children (mean +/- SE; P < 0.0001, Wilcoxon-test). Previous studies demonstrated that GH-BP is increased in healthy overweight children. In contrast, in IDDM children, GH-BP was reduced despite a moderate degree of overweight (z-score for weight: +0.94 +/- 0.12; mean +/- SE). Reduced serum GH-BP activity in IDDM children is further accentuated when compared to healthy children with a similar degree of overweight (22.8 +/- 0.5%; n = 44). Based on this novel finding, we conclude that decreased GH receptor density may explain reduced growth velocity despite increased secretion of GH in some IDDM children.
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PMID:The serum growth hormone-binding protein is reduced in young patients with insulin-dependent diabetes mellitus. 842 Oct 83

The aim of this study was to investigate the regulation of various proteins of the GHIGF axis during progression of liver failure and to search for potential prognostic markers of functional hepatic reserve. Serum levels of growth hormone (GH) and high affinity growth hormone binding protein (GHBP), insulin-like growth factor I (IGF-I) and IGF binding proteins (IGFBP) -1, -2 and -3 were determined in patients with liver cirrhosis. A continuous decline in the concentrations of IGF-I, IGFBP-3 and serum GH-binding activity (GHBP) was observed during progression of cirrhosis and the data correlated significantly with choline esterase, total serum protein and the Child score. In addition, GHBP showed a significant correlation with the enzymatic activity of glutamate dehydrogenase or transaminases and seems so to be influenced by the degree of liver cell damage. In contrast, IGFBP-1 and IGFBP-2 levels were significantly elevated in preterminal disease suggesting an upregulatory mechanism is still effective in this situation. Only when liver function had markedly deteriorated, the serum levels of these two parameters decreased again, possibly due to an impaired synthesis. The excellent correlation between the serum levels of IGF-I (r = -0.64, p < 0.001) or IGFBP-3 (r = -0.67, p < 0.001) and the Child score index suggests that they reflect the hepatic functions just as conventional indicators. For an appropriate interpretation of the liver function the measurement of the growth related peptides can be a valuable tool to estimate pathological alteration in the functional hepatic reserve or in the glucose homeostasis.
Exp Clin Endocrinol Diabetes 1995
PMID:Regulation of growth hormone (GH), insulin-like growth factor (IGF)I, IGF binding proteins -1, -2, -3 and GH binding protein during progression of liver cirrhosis. 853 56

Insulin-like growth factors (IGF-I and IGF-II) are produced in most tissues, particularly liver. Via endocrine and paracrine or autocrine mechanisms, they play an essential role in cell proliferation and differentiation and complement the metabolic effects of insulin. Similarities between the effects of insulin and IGF in vitro are largely due to cross-reaction, owing to their structural homology as well as that of their receptors. At physiological concentrations, insulin is not mitogenic. Compared with insulin, IGFs have negligible metabolic effects on hepatocytes or adipocytes. However, the presence of the IGF-I receptor in muscle accounts for IGF physiological effects in vivo on glucose uptake and glycogen synthesis. Moreover, recombinant IGF-I administered subcutaneously to healthy subjects or patients with Type 2 diabetes causes a drop in plasma levels of triglycerides and VLDL as well as cholesterol and LDL, but not HDL, and also increases insulin sensitivity. All these responses reflect IGF-I inhibition of insulin and GH secretion. In biological media, IGF-I and IGF-II are reversibly associated with specific high-affinity (10(9)-10(11) M-1) binding proteins (IGFBP-1 to -6) differing in expression according to tissue of origin and playing a variety of roles in IGF transport and half-lives, delivery of IGFs to their target cells and modulation of IGF interactions with their receptors. In the blood, where IGF concentrations are 1,000 times those of insulin, IGFBP-3 (the major form) binds at least 80% of IGFs as 140-kDa complexes which do not cross the capillary endothelium and therefore prevent the insulin-like action of IGFs. Nevertheless, these circulating IGF reserves may be mobilized in response to metabolic needs via limited proteolysis of IGFBP-3 by serine proteases. In the case of IGFBP-1, whose hepatic synthesis is negatively regulated by insulin, plasma concentrations are subject to extensive nycthemeral variation, rising with fasting and dropping after feeding, which may be involved in controlling the access of free IGF-I to its cellular receptors and hence IGF-I-regulated glucose and amino acid uptake. Therapeutic applications of recombinant human IGF-I, currently under trial in the treatment of growth retardation resulting from GH receptor abnormalities, hypercatabolic states and would repair, may also be envisaged for cases of insulin resistance, particularly type 2 diabetes.
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PMID:The IGF system in metabolism regulation. 858 49


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