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)

Circulating levels and hepatic expression of insulin-like growth factor-binding protein-1 (IGFBP-1) are increased in insulin-deficient streptozotocin (STZ)-diabetic rats. Glucocorticoids stimulate and insulin suppresses hepatocellular expression of IGFBP-1 in vitro. We asked whether increased IGFBP-1 expression in STZ-diabetic animals is due to an effect of insulin deficiency per se or whether insulin deficiency represents a permissive state where glucocorticoids may play an important role in the regulation of IGFBP-1 and other circulating peptides involved in the modulation of IGF bioactivity. Intact female Sprague-Dawley-derived rats and rats undergoing bilateral adrenalectomy (ADNX) were injected with STZ (140 mg/kg) or buffer. Corticosterone acetate (50 mg/kg) or vehicle was administered to diabetic and nondiabetic animals immediately after ADNX and 24 h later. All rats were killed 48 h after surgery and/or STZ administration. Serum [125I]IGF-I-binding activity was increased 4-fold (P < 0.01), and Western ligand and immunoblotting demonstrated that levels of IGFBP-1 were high in intact STZ-diabetic animals. ADNX prevented these effects of STZ-diabetes, and corticosterone treatment restored serum IGF-binding activity and IGFBP-1 to intact diabetic levels. Similarly, Northern analysis demonstrated that the abundance of hepatic IGFBP-1 mRNA was increased 6-fold in intact STZ-diabetic animals (P < 0.01), but not in adrenalectomized diabetic animals. Corticosterone treatment restored hepatic IGFBP-1 mRNA to intact diabetic levels, and serum concentrations of corticosterone correlated with the abundance of IGFBP-1 mRNA (r = 0.475; P < 0.01), indicating that glucocorticoids play an important role in the regulation of expression of IGFBP-1 in insulin-deficient animals. In contrast, neither ADNX nor corticosterone altered the abundance of hepatic IGFBP-1 mRNA levels in nondiabetic animals. This pattern of regulation appeared to be specific; serum levels of immunoreactive IGFBP-2 and -4 tended to rise in adrenalectomized animals, and levels of IGFBP-3 were not affected by either ADNX or corticosterone treatment. Of note, serum levels of IGF-I by RIA were reduced in STZ-diabetic animals compared to control values (168 +/- 16 vs. 587 +/- 55 ng/ml, respectively; P < 0.01), were partially restored toward control values with ADNX (320 +/- 22 ng/ml), and were reduced again by corticosterone treatment (195 +/- 26 ng/ml), indicating that glucocorticoids also contribute to the regulation of IGF-I levels in insulin-deficient animals. The abundance of IGF-I mRNA was reduced in STZ-diabetic animals, and ADNX also partially prevented this effect of diabetes.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Effects of glucocorticoids on circulating levels and hepatic expression of insulin-like growth factor (IGF)-binding proteins and IGF-I in the adrenalectomized streptozotocin-diabetic rat. 769 41

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 are insulin and nutrition. Most of the circulating IGF I is bound to three IGF binding proteins (BP), mostly IGFBP-3, BP-2 and BP-1. IGF I is also produced by many cells in the body where it exerts autocrine and/or paracrine effects. IGF I has a specific receptor on most cells, the so-called type 1 IGF receptor. When IGF I is administered intravenously as a bolus it leads to acute hypoglycaemia in a similar way to insulin and mainly with the insulin receptor. Chronic administration of IGF I to hypophysectomized or diabetic rats leads to prominent anabolic effects and growth. In this manuscript, metabolic and endocrine effects of recombinant IGF I are discussed. Recombinant IGF I therapy increases energy expenditure and lipid oxidation and decreases proteolysis and protein oxidation. These effects occur despite a partial inhibition of insulin and growth hormone secretion. The therapeutic spectrum of recombinant IGF I, consisting of inhibition of catabolism, stimulation of anabolism, decreases of triglyceride and cholesterol levels and a striking increase in insulin sensitivity, renders IGF I a very interesting, powerful tool for insulin-resistant states such as non-insulin-dependent diabetes mellitus.
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PMID:Recombinant human insulin-like growth factor-I: a therapeutic challenge for diabetes mellitus. 782 34

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

As previously reported, activation of the adrenocorticotropic hormone (ACTH)-adrenal cortical axis in rats with insulin-dependent diabetes mellitus (IDDM) reduces their growth and circulating insulin-like growth factor-I (IGF-I) levels and induces a resistance to growth hormone (GH) and IGF-I. The studies reported herein were conducted to determine whether the pituitary and/or adrenal gland influence the changes in basal and GH-stimulated serum concentrations of IGF-binding proteins (IGFBPs) in rats with IDDM. Male rats were made diabetic by injections of streptozotocin. Intact nondiabetic (NonDb), diabetic (Db), hypophysectomized diabetic (HxDb), and adrenalectomized diabetic (AxDb) rats were injected twice daily with 50 micrograms porcine (p) GH or with 0.9% saline for 2 weeks following the surgeries. Changes in serum IGFBP concentrations were determined by Western ligand- or immuno-blot analysis. Neither IGFBP-5 nor -6 was detected in any of the treatment groups. Induction of IDDM increased serum concentrations of IGFBP-1 and -2 and reduced those of IGFBP-3 and -4. Although serum IGFBP-1 and -2 concentrations remained elevated in the HxDb rats compared with the NonDb controls, IGFBP-1 levels were reduced compared with those in the Db controls. Serum IGFBP-3 and -4 were reduced to levels below those in Db controls. Although IGFBP-3 and -4 concentrations were elevated to normal in AxDb rats, the IGFBP-2 concentration was increased above those in both NonDb and Db rats and the IGFBP-1 concentration was reduced. Administration of pGH increased serum IGFBP-4 concentrations in all groups and IGFBP-3 concentrations in all groups except the Db. In addition, pGH reduced the concentration of IGFBP-1 in HxDb rats and nearly abolished it in AxDb rats, but had no effect on IGFBP-1 concentration in NonDb or Db rats. Administration of corticosterone (B; 25 micrograms/ml of 0.9% saline drinking water) to AxDb rats restored Db-like profiles of all IGFBPs. The refractoriness of Db rats to pGH is associated with a failure of the hormone to elevate IGFBP-2 and -3 titers and to reduce those of IGFBP-1. Adrenal B production appears to be responsible for this resistance to GH. However, the elevated IGFBP-2 concentration in Db rats does not appear to be due to B or any other pituitary-controlled or -derived factors. Impaired growth was associated with substantially reduced IGFBP-3 concentrations and elevated IGFBP-1, whereas growth restoration was associated with the opposite changes.
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PMID:Regulation of insulin-like growth factor-binding proteins in rats with insulin-dependent diabetes mellitus. 853 61

A number of dramatic changes have been documented in the insulin-like growth factors (IGFs-I and -II) and their binding proteins (IGFBPs) during pregnancy. In this study we have tested the hypothesis that a failure of the normal proteolytic modification of IGFBP-3 is responsible for gestational diabetes by examining serum samples taken in the third trimester from 29 women with uncomplicated pregnancies, 21 women with established Type 1 diabetes and 20 women with gestational diabetes. Analysis of IGFBP-3 by Western immunoblotting revealed that it was present in a modified form, migrating at around 29 kDa, in the circulation of all of the women investigated. Semiquantification of the activity of the protease which modifies the IGFBP-3 demonstrated considerable variation between individuals in their ability to fragment radiolabelled IGFBP-3 following a 45-min co-incubation. Surprisingly, in one individual (with gestational diabetes) there was no detectable protease activity even though her endogenous IGFBP-3 had been modified. However, overall there was no clear-cut difference in protease activity between the different groups. Radioimmunometric analysis of IGF-I revealed significantly higher levels in women with gestational diabetes than either of the other two groups (P < 0.05). Similarly IGFBP-3 levels were also increased in these same women (P < 0.05). In contrast, IGF-II levels did not alter between the three groups. In conclusion, our hypothesis was not supported by these data and gestational diabetes was found not to be associated with any reduction in the activity of the circulating IGFBP-3 protease which could have decreased the availability of the IGF nor with any alteration in IGFs which could explain the onset of diabetes in these women.
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PMID:Could abnormalities in insulin-like growth factors and their binding proteins during pregnancy result in gestational diabetes? 854 22

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

We have examined the regulation of endothelial IGFBP-3 production by IGF-I and TGF-beta, two growth factors thought to play a major roles in the complications of diabetes mellitus. In addition, we developed a sensitive method for IGFBP-3 mRNA quantitation by adapting the fluorescent modification of the competitive PCR strategy. Our results using both Northern analysis and the fluorescent competitive PCR method indicate that: (1) IGFBP-3 mRNA is increased 2- to 10-fold by IGF-I and maximally reduced to 20% of control by TGF-beta; (2) the changes in mRNA levels correlate with the levels of IGFBP-3 protein secreted into the media by these cells; (3) the induction of IGFBP-3 mRNA and protein by IGF-I analogs was directly related to their ability to bind to the type I IGF receptor, reflecting an IGF-I receptor-mediated process; and (4) steady state IGFBP-3 mRNA levels did not change significantly after a 6 h incubation with actinomycin D in the presence or absence of the growth factors suggesting that the observed IGF-I/TGF-beta effects occur at the level of gene transcription rather than mRNA stability.
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PMID:Regulation of endothelial IGFBP-3 synthesis and secretion by IGF-I and TGF-beta. 871 44

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

The objectives were to investigate whether insulin-dependent diabetes mellitus disrupts production of estradiol and activity of the insulin-like growth factor (IGF)-I system in individual ovarian follicles during the preovulatory period of the estrous cycle. Diabetes mellitus was induced with streptozocin (150 mg/kg) in seven cyclic gilts at 180 +/- 5 days of age. On Day 12 of the estrous cycle, insulin replacement therapy was withdrawn from three gilts and continued in four; four gilts served as normal controls. After ovary removal on Day 18, all follicles > or = 3 mm diameter were dissected free and cultured for 6 h in the presence of 280 ng testosterone for assessment of estradiol and IGF-I production and binding protein activity. Treatments did not affect corpora lutea number (15.4 +/- 0.8) or serum estradiol (5.8 +/- 0.8 pg/ml) on Day 18. There were no differences for any measure of follicular development between normal and insulin-treated diabetic gilts. Untreated diabetic gilts, compared to normal and insulin-treated diabetic gilts, had fewer total visible follicles (22.7 vs. 61.3 and 63.3; SEM = 8; p < 0.01) and reduced follicular diameter (3.4 vs. 4.4 and 4.2 mm; SEM = 0.3; p < 0.0001), respectively. Untreated diabetic gilts had a greater percentage of macroscopically atretic follicles than normal and insulin-treated diabetic gilts (75% vs. 47% and 36%; SEM = 10; p < 0.05). Untreated diabetes mellitus lowered estradiol (p < 0.01); however, effects of treatment on estradiol production were not significant when diameter was part of statistical models. When contents of IGF-I in follicular fluid and conditioned medium were summed after 6 h of culture, untreated diabetic pigs had lower IGF-I at all follicle diameters than pigs in the other treatments (p < 0.05). IGF binding protein (BP) activity was affected by diabetes mellitus, with untreated diabetic pigs having greater IGFBP-1 activity in medium and with both diabetic groups having greater IGFBP-2 activity in follicular fluid (p < 0.05). Activity of IGFBP-1 predominated in conditioned medium, and IGFBP-2 activity predominated in follicular fluid. IGFBP-3 was decreased in follicular fluid of atretic follicles and in medium of atretic follicles in all except the insulin-treated diabetic gilts; in these gilts it was increased in atretic follicles (treatment by atresia interaction; p < 0.05). In conclusion, estradiol was most related to size of the follicle; however, lowering of IGF-I regardless of follicle diameter and alterations in IGFBP activity suggest that diabetes affects IGF-I and its binding proteins differently from estradiol production. These alterations may explain reduced follicular growth and increased follicular atresia in diabetic pigs.
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PMID:Depletion of insulin in streptozocin-induced-diabetic pigs alters estradiol, insulin-like growth factor (IGF)-I and IGF binding proteins in cultured ovarian follicles. 887 89


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