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Hansenne, Isabelle Sylvie, Chantal Renard i Vincent Geenen. "Igf2 expression is required for complete tolerance to insulin (128.19)". Journal of Immunology 178, nr 1_Supplement (1.04.2007): S213—S214. http://dx.doi.org/10.4049/jimmunol.178.supp.128.19.
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Abstract All members of insulin gene family are transcribed in human thymus according a hierarchy whereby IGF2 expression (thymic epithelial cells/TEC) exceeds IGF1 (macrophages), which exceeds INS (medullary TEC). Type 1 and type 2 IGF receptors are expressed by thymic T-cell populations. To further study the expression of IGF-2 in thymus, the dominance of this factor was compared to insulin, while ontogenesis of Igf2, insulin1 and insulin2 transcription was studied in Balb/c pancreas and thymus. In 4-wk old thymi, IGF-2 concentration is higher than insulin content. Ontogenesis of Igf2, insulin1 and insulin2 transcription from E13 to post-natal day 2 does not differ in Balb/c thymus and pancreas. In a second step, tolerance to IGF-2 and insulin was assessed by immunization of Igf2−/− mice. The profile of B-cell response in Igf2−/− mice immunized with IGF-2 evidenced a T-dependent profile of anti-IGF-2 antibodies that was absent in Igf2+/+ mice. This T-dependent isotype switch indicates the presence of specific anti-IGF-2 CD4+ T cells. Cloning of these T cells failed because Igf2−/− CD4+ T cells exhibit a low rate of proliferation in presence of IGF-2. After immunization with insulin, Igf2−/− mice developed a significantly higher humoral response against insulin, indicating that Igf2 expression is necessary for complete tolerance to insulin.
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Ballard, F. J., M. Ross, F. M. Upton i G. L. Francis. "Specific binding of insulin-like growth factors 1 and 2 to the type 1 and type 2 receptors respectively". Biochemical Journal 249, nr 3 (1.02.1988): 721–26. http://dx.doi.org/10.1042/bj2490721.
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1. Competitive binding and receptor cross-linking experiments have been used to examine the receptor-ligand interactions between three bovine insulin-like growth factors (IGF) and monolayer cultures of myoblasts and fibroblasts. 2. Labelled IGF-2 bound predominantly to the type 2 receptor with negligible label cross-linked to the type 1 receptor, notwithstanding the ability of IGF-2 to compete effectively for the binding of IGF-1 to the type 1 receptor. Approx. 100-fold higher concentrations of IGF-1 or the N-terminal truncated (des-Gly-Pro-Glu) IGF-1 (-3N:IGF-1) were required to produce competition equivalent to IGF-2. 3. All IGF peptides, but especially IGF-1, enhanced the binding of labelled IGF-2 to the type 2 receptor of lung fibroblasts. This unusual effect was probably a consequence of the displacement of labelled IGF-2 otherwise bound to a medium protein, a conclusion supported by the demonstration of a 38 kDa membrane protein cross-linked to labelled IGF-2. 4. Both IGF-1 and -3N:IGF-1 bound only to the type 1 IGF receptor in L6 myoblasts, rat vascular smooth-muscle cells and human lung fibroblasts. The peptides competed for labelled IGF-1 binding with potencies in the order -3N:IGF-1 greater than IGF-1 greater than IGF-2 much greater than insulin. Since the IGF peptides were equipotent in skin fibroblasts, it was proposed that the apparently higher affinity of -3N:IGF-1 for receptors in the other cell types was instead a consequence of a low affinity of this peptide for the competing 38 kDa binding protein.
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Louis, Céline, Chantal Renard, Alain Bosseloir, Ilse Weets, Frans Gorus i Vincent Geenen. "Humoral and cellular immune responses to IGF-2 in type 1 diabetes (128.21)". Journal of Immunology 178, nr 1_Supplement (1.04.2007): S214. http://dx.doi.org/10.4049/jimmunol.178.supp.128.21.
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Abstract Background IGF-2 is the dominant member of insulin family expressed in the thymus, Igf2 expression contributes to complete tolerance of insulin, and Igf2 transcription is defective in the thymus of diabetes-prone BB rats. Objectives To evaluate the immunological tolerance to IGF-2 in T1D patients; andTo analyse the type of cellular response induced by IGF-2 B11-25, the homologous sequence of Insulin B9-23, a major T1D auto-antigen. Results Using a sensitive and specific radio-binding assay, the presence of autoantibodies against IGF-2 was investigated in 100 newly diagnosed T1D patients and 100 healthy controls. No significant difference appeared between the two groups.We also investigated the profile of IL-10/IFN-γ secretion following presentation of Insulin B9-23 and IGF-2 B11-25 to PBMCs from T1D patients and healthy controls. Compared to Insulin B9-23 in ELISpot, ELISA and real-time RT-PCR, the presentation of IGF-2 B11-25 induced a regulatory/tolerogenic profile with a significantly higher increase of IL10 transcription and IL-10 secretion. Conclusions The very strong tolerance to IGF-2 is associated to active regulatory properties that might be exploited for development of a tolerogenic self-vaccine against T1D. (Supported by the Belgian NFSR, Walloon Region TOLEDIAB project, and FP6 Euro-Thymaide Integrated Project)
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Rosenzweig, Steven A. "The Continuing Evolution of Insulin-like Growth Factor Signaling". F1000Research 9 (23.03.2020): 205. http://dx.doi.org/10.12688/f1000research.22198.1.
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The insulin-like growth factors (IGFs; IGF1/IGF2), known for their regulation of cell and organismal growth and development, are evolutionarily conserved ligands with equivalent peptides present in flies (D. melanogaster), worms (C. elegans) among others. Two receptor tyrosine kinases, the IGF1 receptor and the insulin receptor mediate the actions of these ligands with a family of IGF binding proteins serving as selective inhibitors of IGF1/2. This treatise reviews recent findings on IGF signaling in cancer biology and central nervous system function. This includes overexpression of IGF1 receptors in enhancing tumorigenesis, acquired resistance and contributions to metastasis in multiple cancer types. There is accumulating evidence that insulin resistance, a hallmark of type 2 diabetes, occurs in the central nervous system, independent of systemic insulin resistance and characterized by reduced insulin and IGF1 receptor signaling, and may contribute to dementias including Alzheimer’s Disease and cognitive impairment. Controversy over the role(s) of IGF signaling in cancer and whether its inhibition would be of benefit, still persist and extend to IGF1’s role in longevity and central nervous system function.
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Al-janaby, Mohammed Salih, Mohammed Qais Al-ani i Marrib N. Rasheed. "RELATIONSHIP BETWEEN SOME IMMUNOLOGICAL FACTORS AND TYPE 2 DIABETES MELLITUS IN IRAQI PATIENTS". Asian Journal of Pharmaceutical and Clinical Research 11, nr 6 (7.06.2018): 489. http://dx.doi.org/10.22159/ajpcr.2018.v11i6.25881.
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Objective: To determine whether elevated levels of the inflammatory markers interleukin 6 (IL-6), interleukin 8 (IL-8) and insulin – like growth factor-1 are associated with development of type 2 DM in Iraqi sample.Methods: A total number of 150 samples in this study, including 75 diabetes mellitus patients and 75 healthy people (control) This study was conducted from August 2016 to February 2017. All samples were collected from Anbar city, Iraq. Serum concentrations of IL-6, IL-8 and IGF. were determined using a commercially available enzyme-linked immune sorbent assay (ELISA).Results: The results of the present study showed that there was a difference in the mean values of IL-6, IL-8 and IFG between the group of patients with type 2 diabetes and the control group The results showed a negative correlation between IL-6 and IL-8, while the correlation between IL-6 and IGF and between IL -8 and IGF was showed positive correlationConclusion: Elevated levels of IL-6 and IL-8 predict the development of type 2 DM. These data support a possible role for inflammation in diabetogenesis. Type 2 diabetes as well as pre-diabetic states, including impaired fasting glucose and impaired glucose tolerance, are associated cross-sectionally with altered circulating levels of IGF-I . decline in the levels of IGF-I dependent on duration of diabetes in non insuline dependent diabetic patients.
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Ballard, F. J., L. C. Read, G. L. Francis, C. J. Bagley i J. C. Wallace. "Binding properties and biological potencies of insulin-like growth factors in L6 myoblasts". Biochemical Journal 233, nr 1 (1.01.1986): 223–30. http://dx.doi.org/10.1042/bj2330223.
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Protein synthesis in rat L6 myoblasts is stimulated and protein breakdown inhibited in a co-ordinate manner by insulin-like growth factors (IGF) or insulin. For both processes, bovine IGF-1 was somewhat more potent than human IGF-1, which was effective at a tenth the concentration of insulin, rat IGF-2 or human IGF-2. A similar order of potency is noted when DNA synthesis or protein accumulation is monitored over a 24 h period, but between 20- and 50-fold higher concentrations of each growth factor are required than those needed to produce effects in the 4 h protein-synthesis or -breakdown measurements. Binding experiments with labelled human or bovine IGF-1 as ligand demonstrated competition at concentrations of IGF-2, especially human IGF-2, lower than that of either IGF-1 preparation. This pattern was much more pronounced when the radioligand was either human IGF-2 or rat IGF-2. Insulin competed 10-15% for the binding of labelled IGF-1, but not at all with labelled IGF-2. Ligand-receptor cross-linking experiments showed that labelled bovine IGF-1 bound approximately equally to the type 1 IGF receptor (Mr 130000 after reduction) and to the type 2 IGF receptor (Mr 270000 after reduction), and that unlabelled IGF-1 competed equally with radioligand binding to both receptors. On the other hand, rat IGF-2 competed more effectively for binding to the type-2 receptor, and insulin competed only for binding to the type-1 receptor. Further cross-linking experiments with rat IGF-2 as radioligand demonstrated binding only to the type-2 receptor and to proteins with Mr values after reduction of 230000 and 200000. This binding was prevented by high rat IGF-2 concentrations, less effectively by bovine IGF-1 and not at all by insulin. The apparently conflicting biological potencies and receptor binding of the different growth factors can be explained if all the biological actions are mediated via the type-1 IGF receptor, rather than through the abundant type-2 receptor.
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Schuller, A. G. P., J. W. van Neck, R. W. Beukenholdt, E. C. Zwarthoff i S. L. S. Drop. "IGF, type I IGF receptor and IGF-binding protein mRNA expression in the developing mouse lung". Journal of Molecular Endocrinology 14, nr 3 (czerwiec 1995): 349–55. http://dx.doi.org/10.1677/jme.0.0140349.
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ABSTRACT The IGFs are important mitogens involved in lung growth and development. The regulation of IGF action depends not only on the expression of IGFs and IGF receptors, but also on the modulation of IGF activity by IGF-binding proteins (IGFBPs). In this study, we describe the mRNA expression of IGF-I, IGF-II, type I IGF receptor, IGFBP-2, IGFBP-4 and IGFBP-5 during mouse lung development as studied by in situ hybridization techniques. The IGF, type I IGF receptor and IGFBP-2, -4 and -5 genes were expressed in developing lung as early as embryonal day 12·5. Expression of IGFBPs-1, -3 and -6 was below detection. IGF and IGFBP-2 mRNAs were expressed both in mesenchymal and epithelial cells. Type I IGF receptor transcripts were also observed throughout the developing lung, with the exception of the epithelial cells of the bronchi after embryonal day 15. Furthermore, mRNA expression of IGFBPs-4 and -5 was noted in neighbouring cell types, and after embryonal day 15, co-expression of the type I IGF receptor and IGFBP-4 transcripts was detected. The observed expression patterns imply that the IGFBP-2, -4 and -5 genes are differentially regulated during embryonic development and suggest that each may have a discrete function. A possible role for IGFBPs-2, -4 and -5 is to participate in the regulation of cell-specific IGF responses during mouse lung development.
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Wasim, H., M. Abdelmonem, S. Samir i A. Salah. "Monitoring Of IGF-1 Levels In Type 2 Diabetic Patients With Macro And Microvascular Complications". American Journal of Clinical Pathology 154, Supplement_1 (październik 2020): S127—S128. http://dx.doi.org/10.1093/ajcp/aqaa161.279.
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Abstract Introduction/Objective Introduction: Type-2 diabetes have a risk factor of multiple complications such as coronary artery diseases (CAD), premature atheroscalerosis and diabetic retinopathy. IGF-1 is regulated by a balance of hormones such as growth hormone and insulin. It is important that circulating IGF1 in serum has normal levels to maintain glucose metabolism. Objectives: Monitoring of IGF-1levels in T2DM with macrovascular complications (CVD) and microvascular complications (retinopathy). Methods Subjects and methods: The collection of samples started in June 2018 and ended in December 2018. A total of 114 subjects were enrolled in this study; 98 clinically diagnosed T2D patients who were recruited from the outpatient clinic of the National Institute for Diabetes and Endocrinology “NIDE”, in addition to 16 healthy comparable control subjects (without diabetes). The subjects divided into 3 groups. Group 1; a population of 44 T2D patients with macrovascular complications (28 females and 16 males), the mean age was 57.4 years. Group 2; a population of 54 T2D patients with microvascular complicatios (34 females and 20 males), the mean age was 59.1 years. Group 3; a population of 16 healthy subjects (12 female and 4 males), the mean age was 59.2 years. Levels of FBS, C-peptide, HbA1c, Lipid profile, lipoprotein(a), hs-CRP and microalbuminurea were measured in all subjects. Seum concentration of IGF-1 was measured by commercially immunoenzymatic ELIZA method. Results It was found that serum concentration of IGF-1 decreased in diabetic patients groups compared to the control one. The mean±SD of group 1, group 2 and group 3 were (332.2±152.2), (316.9 ±142.2) and (625.4 ± 257.7) respectively. Conclusion It was observed that there was a negative correlation between serum IGF-1 levels in T2D patients compared to the control group. Also, it was found that T2D patients with microvascular complications had lower IGF-1 levels than patients with macrovascular ones. It seems that IGF-1 strongly involved in the incidence and pathogenesis of T2DM complications.
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Narayanan, Ram P., Matthew Gittins, Kirk W. Siddals, Robert L. Oliver, Julie E. Hudson, Anne White, Paul Durrington, Robert R. Davies, Martin K. Rutter i J. Martin Gibson. "Atorvastatin administration is associated with dose-related changes in IGF bioavailability". European Journal of Endocrinology 168, nr 4 (kwiecień 2013): 543–48. http://dx.doi.org/10.1530/eje-12-0844.
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ObjectiveIGF levels, their binding proteins (IGFBPs) and high-dose statin therapy have been linked to the development of diabetes. We aimed to identify whether atorvastatin caused dose-related changes in IGF proteins.Design and methodsWe measured IGF1, IGF2, IGFBP1 and IGFBP3 concentrations at baseline, 6 and 12 months in Protection Against Nephropathy in Diabetes with Atorvastatin trial participants with type 2 diabetes randomised to 10 mg (n=59) vs 80 mg (n=60) of atorvastatin (n=119; mean (s.d.): age 64 (10) years; 83% male; HbA1c 61 (10) mmol/mol; blood pressure 131/73 mmHg).ResultsAtorvastatin was associated with overall reductions in circulating IGF1, IGF2 and IGFBP3 concentrations (P<0.05 for all changes). The adjusted mean (95% CI) between-group differences that indicate dose-related changes in IGF proteins were not significant for IGF1: −3 (−21 to 14) ng/ml; IGF2: −23 (−65 to 18) ng/ml and IGFBP3: −0.34 (−0.71 to 0.03) μg/ml, negative values indicating numerically greater lowering with high dose. The IGFBP1 concentration did not change with atorvastatin therapy overall but the adjusted mean (95% CI) between-group difference indicating a dose-related change in log IGFBP1 was highly significant −0.41 (−0.69 to 0.13, P=0.004).ConclusionIGF1, IGF2 and IGFBP3 concentrations decreased following atorvastatin therapy. A differential effect of low- vs high-dose atorvastatin on IGFBP1 concentrations was observed with likely implications for IGF bioavailability. The dose-related differential impact of atorvastatin treatment on concentration of IGF proteins merits investigation as a mechanism to explain the worsening of glucose tolerance with statin therapy.
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Kirk, S. P., M. A. Whittle, J. M. Oldham, P. M. Dobbie i J. J. Bass. "GH regulation of the Type 2 IGF receptor in regenerating skeletal muscle of rats". Journal of Endocrinology 149, nr 1 (kwiecień 1996): 81–91. http://dx.doi.org/10.1677/joe.0.1490081.
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Abstract GH enhances skeletal muscle growth, and IGF-II peptide is highly expressed during regeneration. We have therefore investigated the effect of GH administration on IGF-II binding and expression in regenerating rat skeletal muscle using the techniques of receptor autoradiography and in situ hybridisation. Notexin, a myotoxin, was injected into the right M. biceps femoris (day 0), causing affected fibres to undergo necrosis followed by rapid regeneration. Animals were administered either GH (200 μg/100 g body weight) or saline vehicle daily. Contralateral muscles were used as regeneration controls. GH administration during regeneration resulted in significant increases in body weight, and damaged and undamaged muscle weights (P<0·001). IGF-II expression, which was examined in regenerating fibres, survivor fibres and undamaged fibres, varied according to tissue type (P< 0·001). Specifically, IGF-II expression in regenerating fibres was elevated relative to control and survivor fibres after day 3 (P<0·05), with a peak on day 9 (P<0·001). GH did not affect IGF-II message levels. 125I-IGF-II binding in regenerating muscle was examined in the same fibre types as well as in connective tissue. 125I-IGF-II binding in regenerating fibres was higher (P<0·001) than in other tissue types on day 5. GH administration increased 125I-IGF-II binding in all damaged muscle tissues on day 5 (P<0·001, regenerating fibres; P<0·01, others). We believe that this shows for the first time an effect of GH on the Type 2 IGF receptor in regenerating skeletal muscle. Journal of Endocrinology (1996) 149, 81–91
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Narayanan, Ram P., Bo Fu, Adrian H. Heald, Kirk W. Siddals, Robert L. Oliver, Julie E. Hudson, Antony Payton i in. "IGFBP2 is a biomarker for predicting longitudinal deterioration in renal function in type 2 diabetes". Endocrine Connections 1, nr 2 (listopad 2012): 95–102. http://dx.doi.org/10.1530/ec-12-0053.
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ObjectiveInsulin-like growth factors are implicated in the development of diabetic nephropathy. IGF-binding protein 2 (IGFBP2) and IGF2 are expressed in the kidney, but their associations with diabetic nephropathy are unclear. We therefore tested the hypothesis that circulating levels of IGF2 and IGFBP2 predict longitudinal renal function in individuals with type 2 diabetes.Design and methodsIGFBP2 and IGF2 measurements were performed in 436 individuals (263 males) with type 2 diabetes. Linear mixed-effect regression analysis was used to model the relationship between plasma IGFBP2 concentration and longitudinal changes in estimated glomerular filtration rate (eGFR) over an 8-year period. Analyses were also performed for IGF1, IGF2, IGFBP1 and IGFBP3 concentrations as predictors of longitudinal renal outcomes.ResultsHigh IGFBP2 concentration at baseline was associated with a decreased eGFR over an 8-year period (β=−0.02, (95% confidence interval −0.03 to −0.01), P<0.001). High IGFBP1, IGFBP2 and IGFBP3 were also associated with low baseline eGFR concentration.ConclusionThis study demonstrates that IGFBP2 is a predictor of longitudinal deterioration of renal function in type 2 diabetes.
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Cohen, Dara Hope, i Derek LeRoith. "Obesity, type 2 diabetes, and cancer: the insulin and IGF connection". Endocrine-Related Cancer 19, nr 5 (październik 2012): F27—F45. http://dx.doi.org/10.1530/erc-11-0374.
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Epidemiological studies suggest a positive association between obesity and type 2 diabetes mellitus (T2D) with the risk of cancer and cancer-related mortality. Insulin resistance, hyperinsulinemia, increased levels of IGF, elevated levels of steroid and peptide hormones, and inflammatory markers appear to play a role in the connection between these different diseases. Medications, such as metformin and exogenous insulin, used to treat T2D may affect the risk of cancer and cancer-related mortality. Newer therapies targeting the insulin and IGF1 systems are being developed for use in cancer therapy.
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McCusker, RH, i J. Novakofski. "Zinc partitions IGFs from soluble IGF binding proteins (IGFBP)-5, but not soluble IGFBP-4, to myoblast IGF type 1 receptors". Journal of Endocrinology 180, nr 2 (1.02.2004): 227–46. http://dx.doi.org/10.1677/joe.0.1800227.
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Zinc (Zn(2+)), a multifunctional micronutrient, was recently shown to lower the affinity of cell-associated insulin-like growth factor (IGF) binding protein (IGFBP)-3 and IGFBP-5 for both IGF-I and IGF-II, but to increase the affinity of the cell surface type 1 IGF receptor (IGF-1R) for the same two ligands. However, there is a need for data concerning the effects of Zn(2+) on soluble IGFBPs and the type 2 IGF receptor (IGF-2R). In the current work, we demonstrate that Zn(2+) affects the affinity of IGFBP-5 secreted by myoblasts but not IGFBP-4. Zn(2+), at physiological levels, depressed binding of both IGF-I and IGF-II to IGFBP-5, affecting (125)I-IGF-I more than (125)I-IGF-II. Both (125)I-IGF-I and (125)I-IGF-II bound to high and low affinity sites on IGFBP-5. Zn(2+) converted the high affinity binding sites of IGFBP-5 into low affinity binding sites. An IGF-I analog, (125)I-R(3)-IGF-I, did not bind to the soluble murine IGFBP-5. Zn(2+) also decreased the affinity of the IGF-2R on L6 myoblasts. In contrast, Zn(2+) increased IGF-I, IGF-II and R(3)-IGF-I binding to the IGF-1R by increasing ligand binding affinity on both P(2)A(2a)-LISN and L6 myoblasts. Soluble IGFBP-5 and IGFBP-4 depressed the binding of (125)I-IGF-I and (125)I-IGF-II to the IGF-1R, but did not affect binding of (125)I-R(3)-IGF-I. By depressing the association of the IGFs with soluble IGFBP-5, Zn(2+) partitioned (125)I-IGF-I and (125)I-IGF-II from soluble IGFBP-5 onto cell surface IGF-1Rs. This effect is not seen when soluble L6-derived IGFBP-4 is present in extracellular fluids. We introduce a novel mechanism by which the trace micronutrient Zn(2+) may alter IGF distribution, i.e. Zn(2+) acts to increase IGF-1R binding at the expense of IGF binding to soluble IGFBP-5 and the IGF-2R.
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Højlund, Kurt, Henning Beck-Nielsen, Allan Flyvbjerg i Jan Frystyk. "Characterisation of adiponectin multimers and the IGF axis in humans with a heterozygote mutation in the tyrosine kinase domain of the insulin receptor gene". European Journal of Endocrinology 166, nr 3 (marzec 2012): 511–19. http://dx.doi.org/10.1530/eje-11-0790.
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ObjectiveLow levels of adiponectin, IGF-binding protein 1 (IGFBP1) and IGFBP2 and high levels of leptin correlate with several indices of insulin resistance and risk of type 2 diabetes. However, in insulin receptoropathies, plasma adiponectin is paradoxically increased despite severe insulin resistance, whereas the IGF axis is sparsely described. Here, we aimed to characterise the multimeric distribution of adiponectin and the IGF axis in humans with a heterozygous INSR mutation (Arg1174Gln).MethodsBlood samples obtained from six Arg1174Gln carriers and ten lean, healthy controls before and after a euglycaemic–hyperinsulinaemic clamp were examined for plasma adiponectin multimers, leptin, total IGF1, IGF2, free IGF1, IGFBP1 and IGFBP2.ResultsDespite tenfold elevated fasting insulin and marked insulin resistance in Arg1174Gln carriers, the levels of total adiponectin, leptin, IGFBP1 and IGFBP2 were similar to those observed in controls, while total IGF1, IGF2 and free IGF1 levels were increased. The relative fraction of high-molecular weight adiponectin was increased, whereas both the absolute concentration and the fraction of low-molecular weight adiponectin were decreased in Arg1174Gln carriers. Interestingly, exogenous insulin failed to suppress total adiponectin in Arg1174Gln carriers, but reduced IGFBP1 and increased IGFBP2 as in controls.ConclusionThe normal levels of adiponectin, IGFBP1 and IGFBP2 in the face of highly elevated insulin levels suggest an impaired ability of insulin to suppress markers of common insulin resistance in carriers of a dominant-negative INSR mutation. However, together with the adaptive increases in IGF1 and IGF2 and a potentially improved distribution of adiponectin multimers, these changes may contribute to rescue insulin action in insulin receptor-deficient individuals.
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Ross, M., G. L. Francis, L. Szabo, J. C. Wallace i F. J. Ballard. "Insulin-like growth factor (IGF)-binding proteins inhibit the biological activities of IGF-1 and IGF-2 but not des-(1-3)-IGF-1". Biochemical Journal 258, nr 1 (15.02.1989): 267–72. http://dx.doi.org/10.1042/bj2580267.
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(1) Many cell types secrete insulin-like growth factor (IGF)-binding proteins that can be expected to sequester free IGF and modify the biological activities of the growth factors. (2) A binding protein purified from bovine kidney (MDBK) cells potently inhibited the ability of IGF-2 to stimulate DNA synthesis or protein accumulation as well as to reduce rates of protein breakdown in chick embryo fibroblasts. The binding protein did not influence the biological activities of des-(1-3)-IGF-1, while effects on IGF-1 were intermediate. Since the chick embryo fibroblasts contain only the type 1 IGF receptor, the MDBK-cell binding protein must have reduced the accessibility of IGF-2 and IGF-1 to that receptor. Binding to the type 2 receptor on L6 myoblasts was also inhibited. (3) Inhibiting effects on both protein breakdown responsiveness to IGF and IGF binding to cell receptors were also observed with human amniotic fluid binding protein, although here IGF-1 and IGF-2 were equipotent. These results contrast with stimulatory responses on different IGF-1 actions of the same binding protein reported previously [Elgin, Busby & Clemmons (1987) Proc. Natl. Acad. Sci. U.S.A. 84, 3254-3258]. (4) The biological potencies of IGF-1, IGF-2 and des-(1-3)-IGF-1 correlate inversely with their binding to proteins released into the medium by cells, so that the enhanced potency of des-(1-3)-IGF-1 is a consequence of it not binding to purified binding proteins or those released by cultured cells.
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Pratipanawatr, Thongchai, Wilailak Pratipanawatr, Clifford Rosen, Rachele Berria, Mandeep Bajaj, Kenneth Cusi, Lawrence Mandarino, Sangeta Kashyap, Renata Belfort i Ralph A. DeFronzo. "Effect of IGF-I on FFA and glucose metabolism in control and type 2 diabetic subjects". American Journal of Physiology-Endocrinology and Metabolism 282, nr 6 (1.06.2002): E1360—E1368. http://dx.doi.org/10.1152/ajpendo.00335.2001.
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The effects of insulin-like growth factor I (IGF-I) and insulin on free fatty acid (FFA) and glucose metabolism were compared in eight control and eight type 2 diabetic subjects, who received a two-step euglycemic hyperinsulinemic (0.25 and 0.5 mU · kg−1 · min−1) clamp and a two-step euglycemic IGF-I (26 and 52 pmol · kg−1 · min−1) clamp with [3-3H]glucose, [1-14C]palmitate, and indirect calorimetry. The insulin and IGF-I infusion rates were chosen to augment glucose disposal (Rd) to a similar extent in control subjects. In type 2 diabetic subjects, stimulation of Rd (second clamp step) in response to both insulin and IGF-I was reduced by ∼40–50% compared with control subjects. In control subjects, insulin was more effective than IGF-I in suppressing endogenous glucose production (EGP) during both clamp steps. In type 2 diabetic subjects, insulin-mediated suppression of EGP was impaired, whereas EGP suppression by IGF-I was similar to that of controls. In both control and diabetic subjects, IGF-I-mediated suppression of plasma FFA concentration and inhibition of FFA turnover were markedly impaired compared with insulin ( P < 0.01–0.001). During the second IGF-I clamp step, suppression of plasma FFA concentration and FFA turnover was impaired in diabetic vs. control subjects ( P < 0.05–0.01). Conclusions: 1) IGF-I is less effective than insulin in suppressing EGP and FFA turnover; 2) insulin-resistant type 2 diabetic subjects also exhibit IGF-I resistance in skeletal muscle. However, suppression of EGP by IGF-I is not impaired in diabetic individuals, indicating normal hepatic sensitivity to IGF-I.
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Fournier, Mario, i Michael I. Lewis. "Influences of IGF-I gene disruption on the cellular profile of the diaphragm". American Journal of Physiology-Endocrinology and Metabolism 278, nr 4 (1.04.2000): E707—E715. http://dx.doi.org/10.1152/ajpendo.2000.278.4.e707.
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The impact of a targeted disruption of the Igf1 gene, encoding the insulin-like growth factor I (IGF-I), on diaphragm (DIA) cellularity was studied in 2-mo-old homozygous mutant [IGF-I(−/−)] mice and their wild-type [WT; i.e., IGF-I(+/+)] littermates. DIA fiber types were classified histochemically. DIA fiber cross-sectional areas (CSA) were determined from digitized muscle sections, and fiber succinate dehydrogenase (SDH) activity was determined histochemically using a microdensitometric procedure. An acidic ATPase reaction was used to visualize capillaries. Myosin heavy chain (MyHC) isoforms were identified by SDS-PAGE, and their proportions were determined by scanning densitometry. The body weight of IGF-I(−/−) animals was 32% that of WT littermates. DIA fiber type proportions were unchanged between the groups. The CSAs of types I, IIa, and IIx DIA fibers of IGF-I(−/−) mutants were 63, 68, and 65%, respectively, those of WT animals ( P < 0.001). The DIA thickness and the number of fibers spanning its entire thickness were reduced by 36 and 25%, respectively, in IGF-I(−/−) mice ( P < 0.001). SDH activity was significantly increased in all three types of DIA fibers of IGF-I(−/−) mutants ( P< 0.05). The number of capillaries per fiber was reduced ∼30% in IGF-I(−/−) animals, whereas the capillary density was preserved. The proportions of MyHC isoforms were similar between the groups. Muscle hypoplasia likely reflects the importance of IGF-I on cell proliferation, differentiation, and apoptosis (alone or in combination) during development, although reduced cell size highlights the importance of IGF-I on rate and/or maintenance of DIA fiber growth in the postnatal state. Reduced capillarity may result from both direct and indirect influences on angiogenesis. Improved oxidative capacity likely reflects DIA compensatory mechanisms in IGF-I(−/−) mutants.
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Mannucci, Edoardo. "Insulin Therapy and Cancer in Type 2 Diabetes". ISRN Endocrinology 2012 (14.11.2012): 1–12. http://dx.doi.org/10.5402/2012/240634.
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Despite the availability of many other agents, insulin is widely used as a treatment for type 2 diabetes. In vitro, insulin stimulates the growth of cancer cells, through the interaction with insulin-like growth factor-1 (IGF-1) receptors and its own receptors. In observational surveys on type 2 diabetes, insulin therapy is associated with an increased incidence of several forms of cancer, although it is difficult to discriminate the effect of confounders from that of insulin itself. Randomized trials do not confirm the increased risk associated with insulin therapy, although they do not allow to rule out some negative effects on specific forms of cancer, at least at higher doses. Among insulin analogues, glargine has a higher affinity for the IGF-1 receptor and a greater mitogenic potency in vitro than human insulin, but it is extensively metabolized in vitro to products with low IGF-1 receptor affinity. Overall, epidemiological studies suggest a possible increase of risk with glargine, with respect to human insulin, only at high doses and for some forms of cancer (i.e., breast). Data from clinical trials do not confirm, but are still insufficient to totally exclude, such increased risk. However, beneficial effects of insulin outweigh potential cancer risks.
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Haeri, Nami Safai, Hussain Mahmud i Mary T. Korytkowski. "Paraneoplastic Hypoglycemia Leading to Insulin Independence in a Patient With Type 1 Diabetes". Journal of the Endocrine Society 5, Supplement_1 (1.05.2021): A1003—A1004. http://dx.doi.org/10.1210/jendso/bvab048.2053.
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Abstract Introduction: Hypoglycemia is a rare paraneoplastic manifestation of several non-islet cell tumors (NICT) that is rarely reported in individuals with diabetes. We report the first case of a patient with type 1 diabetes (T1D) and a recurrent gastrointestinal stromal tumor (GIST) who required discontinuation of all insulin therapy with continuous parenteral glucose infusions to avoid hypoglycemia. Case: The patient is an underweight (BMI 14.9 kg/m2) 59-year-old female with a 24-year history of T1D treated with insulin pump therapy who was diagnosed with GIST in 2003. Following surgical resection with postoperative adjuvant therapy, she remained tumor free until 2012 when she had disease recurrence unresponsive to several tyrosine kinase inhibitors. In 2014, she reported frequent episodes of documented hypoglycemia despite continued reductions in basal insulin infusion rates. Laboratory testing following several hours of insulin discontinuation revealed undetectable insulin and C-peptide levels, low IGF-1, normal IGF-2, and an IGF-2: IGF-1 ratio of 7.86. Thyroid, kidney and adrenal tests were normal. Initiation of prednisone alone then in combination with octreotide did not abate the hypoglycemia. During a hospitalization for hypoglycemia, exogenous insulin therapy was discontinued and 10% dextrose infusions started. Attempts at weaning the dextrose infusions resulted in hypoglycemia, prompting insertion of a PICC line prior to discharge home with continuous 25% dextrose infusions at 40-60 mg per hour. Discussion: NICT hypoglycemia (NICTH) is characterized by excessive tumor production of IGF-2 or pro-IGF-2. The structure of IGF-2 is similar to insulin, allowing cross reactivity at the insulin receptor. IGF binding proteins (IGFBPs) are responsible for transporting IGF-2 in plasma. Abnormal processing of the gene for IGF-2 results in increased production of the more biologically active pro-IGF-2 that does not form a complex with IGFBP3 and is available to interact with insulin receptors. In patients with normal IGF-2 (chronic kidney disease, poor nutritional status), an IGF-2: IGF-1 ratio >3 can be used to confirm NICTH. IGFBP-3 was not measured in this patient but it is likely this was low due to her poor nutritional status. The most definitive treatment for NICTH is resection of the tumor. Pharmacological management can be considered in patients who are not surgical candidates, but is not always successful as was observed in this patient. Conclusion:This is an unusual case of malignancy associated hypoglycemia in a woman with type 1 diabetes who required discontinuation of all insulin therapy as well as continuous dextrose infusions to achieve euglycemia and briefly maintain an acceptable quality of life over a period of several months.
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Noveral, J. P., A. Bhala, R. L. Hintz, M. M. Grunstein i P. Cohen. "Insulin-like growth factor axis in airway smooth muscle cells". American Journal of Physiology-Lung Cellular and Molecular Physiology 267, nr 6 (1.12.1994): L761—L765. http://dx.doi.org/10.1152/ajplung.1994.267.6.l761.
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Insulin-like growth factors (IGFs) mediate cell proliferation and differentiation and bind with high affinities and specificities to IGF receptors and IGF-binding proteins (IGFBPs). We examined the roles of these three groups of proteins in cultured rabbit airway smooth muscle (ASM) cells. Affinity cross-linking of IGF-I and IGF-II to membranes of ASM cells revealed type 1 and type 2 IGF receptors. Western ligand blot analysis of ASM cell-conditioned medium revealed the presence of a single IGFBP band that precipitated with an antibody specific to IGFBP-2. ASM cells secreted radioimmunoassayable IGF-II; however, no IGF-I was detected under the same conditions. Two molecular weight forms of IGF-II were produced by the ASM cells. Exposure of cells to 1,000 ng/ml of IGF-I stimulated them to proliferate to 230 +/- 9.7% of their respective controls. Exposure to 1,000 ng/ml of IGF-II was approximately 40% as effective as exposure to 1,000 ng/ml of IGF-I. Both IGF-I and IGF-II exhibited binding to the type 1 IGF receptor. In summary, IGFs are mitogens for cultured rabbit ASM cells, and their actions are most likely mediated through the type 1 IGF receptor. The ASM cells secrete IGF-II and IGFBP-2, and the latter could modulate the actions of the IGFs in these cells.
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Oldham, J. M., A. K. Hodges, P. N. Schaare, P. C. Molan i J. J. Bass. "Nutritional dependence of insulin-like growth factor (IGF) receptors in skeletal muscle: measurement by light microscopic autoradiography." Journal of Histochemistry & Cytochemistry 41, nr 3 (marzec 1993): 415–21. http://dx.doi.org/10.1177/41.3.8429204.
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To determine the cellular location, capacity, and nutritional sensitivity of insulin-like growth factor (IGF) receptors, we measured the in vitro binding of [125I]-IGFs to skeletal muscle using light microscopic autoradiography. Muscle was collected from 8-month lambs that had received high or low nutrition diets (3% and 1.25% of body weight/day in pellets, respectively). Half of each group had also received growth hormone (0.25 mg/kg/day). Cryosections were incubated with [125I]-IGF alone or with unlabeled IGF-1, IGF-2, or insulin to characterize binding sites as probable Type 1 IGF, Type 2 IGF, or insulin receptors. [125I]-IGF-1 was found to bind to blood vessels and Type 1 receptors in connective tissue (p < or = 0.001), but not to muscle fiber or nerves. In muscle from 6-month lambs that were fed or fasted, [125I]-IGF-1 bound to Type 1 receptors in connective tissue (p < or = 0.01 fed; p < or = 0.05 fasted) and muscle fiber (p < or = 0.05). The binding to connective tissue was also greater in fasted than in fed animals (p < or = 0.05). Binding of [125I]-IGF-2 to the Type 2 receptor was located in blood vessels and connective tissue (p < or = 0.01) and did not alter with fasting. Therefore, these experiments have demonstrated that Type 1 and Type 2 receptors vary in their distribution and nutritional sensitivity in skeletal muscle.
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Read, L. C., F. J. Ballard, G. L. Francis, R. C. Baxter, C. J. Bagley i J. C. Wallace. "Comparative binding of bovine, human and rat insulin-like growth factors to membrane receptors and to antibodies against human insulin-like growth factor-1". Biochemical Journal 233, nr 1 (1.01.1986): 215–21. http://dx.doi.org/10.1042/bj2330215.
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The immunological properties of human, bovine and rat insulin-like growth factors (IGF) and insulin were compared in competitive binding studies with Tr10 and NPA polyclonal antisera raised in rabbits against human IGF-1. Bovine IGF-1 was 11-19% as effective as human IGF-1 in competing for binding with 125I-labelled human IGF-1, whereas IGF-2 reacted poorly and insulin did not compete. Similar competitive binding curves were obtained with the mouse monoclonal anti-(human IGF-1) antibody 3D1, except that bovine IGF-1 showed a severalfold greater affinity for the monoclonal antibody than for either polyclonal antiserum. Membranes isolated from human placenta, sheep placenta and foetal-human liver were used as sources of cellular receptors. In human placental membranes, most of the binding of IGF-1 tracers could be attributed to a type-1 receptor, because insulin inhibited up to 65% of tracer binding. The other two tissues apparently contain only type-2 receptors, as evidenced by the very low potency of bovine or human IGF-1 in competing for binding with IGF-2 tracers and the absence of any competition by insulin. In competition for binding with labelled bovine or human IGF-1 to human placental membranes, bovine IGF-1 had a similar potency to human IGF-1, whereas bovine IGF-1 was more potent in binding studies with tissues rich in type-2 receptors. Rat IGF-2 was considerably less effective than human IGF-2 in competition for receptors on any of the membrane preparations.
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Rasmussen, Søren K., Corinne Lautier, Lars Hansen, Søren M. Echwald, Torben Hansen, Claus T. Ekstrøm, Søren A. Urhammer i in. "Studies of the Variability of the Genes Encoding the Insulin-Like Growth Factor I Receptor and Its Ligand in Relation to Type 2 Diabetes Mellitus1". Journal of Clinical Endocrinology & Metabolism 85, nr 4 (1.04.2000): 1606–10. http://dx.doi.org/10.1210/jcem.85.4.6494.
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Insulin-like growth factor I (IGF-I) is an important regulator of many aspects of growth, differentiation, and development, and as low birth weight has been associated with impaired glucose tolerance and overt type 2 diabetes in adult life, we considered the genes encoding the IGF-I and the IGF-I receptor (IGF-IR) as candidates for low birth weight, insulin resistance, and type 2 diabetes. Here we report the mutational analysis of the coding regions of the IGF-I and IGF-IR performed on genomic DNA from probands of 82 Danish type 2 diabetic families. No mutations predicting changes in the amino acid sequences of the IGF-I or IGF-IR genes were detected, but several silent and intronic polymorphisms were found. The impact of the most prevalent polymorphism, GAG1013GAA of the IGF-IR, was evaluated in a population-based sample of 349 young healthy subjects, where the variant had an allele frequency of 0.44 (95% confidence interval, 0.40–0.48). No significant relationships between this variant and birth weight, birth length, or insulin sensitivity index were detected. In addition, we did not observe any significant differences in allelic frequencies of the codon 1013 variant between 395 type 2 diabetic patients (allele frequency, 0.52; 95% confidence interval, 0.49–0.55) and 238 matched glucose-tolerant control subjects (allelic frequency, 0.47; 95% confidence interval, 0.43–0.50). In conclusion, variability in the coding regions of IGF-I and the IGF-IR does not associate with reduced birth weight, insulin sensitivity index, or type 2 diabetes in the Danish population.
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Wathes, D. Claire, Zhangrui Cheng, Mark A. Fenwick, Richard Fitzpatrick i Joe Patton. "Influence of energy balance on the somatotrophic axis and matrix metalloproteinase expression in the endometrium of the postpartum dairy cow". REPRODUCTION 141, nr 2 (luty 2011): 269–81. http://dx.doi.org/10.1530/rep-10-0177.
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Postpartum dairy cows enter a period of negative energy balance (NEB) associated with low circulating IGF1, during which the uterus must undergo extensive repair following calving. This study investigated the effects of NEB on expression of IGF family members and related genes in the involuting uterus. Cows were allocated to two treatments using differential feeding and milking regimes to produce mild NEB or severe NEB (SNEB). Uterine endometrial samples collected 2 weeks post partum were analysed by quantitative PCR. The expression of IGF-binding protein 4 (IGFBP4) mRNA increased in the endometrium of SNEB cows, with trends towards increased IGFBP1 and reduced IGFBP6 expression. There were no significant differences between treatments in mRNA expression of IGF1, IGF2 or of any hormone receptor studied, but significant correlations across all cows in the expression levels of groups of receptors suggested common regulatory mechanisms: type 1 IGF receptor (IGF1R), IGF2R and insulin receptor (INSR); GHR with ESR1; and ESR2 with NR3C1. The expression of IGF1R and INSR also positively correlated with the circulating urea concentration. Matrix metalloproteinases (MMPs) are important in tissue remodelling and can affect IGF signalling via interaction with IGFBPs. The expression levels of MMP1, MMP3, MMP9 and MMP13 mRNAs all showed major upregulation in the endometrium of cows in SNEB and all except MMP9 were highly correlated with expression of IGFBP4. Alpha(2)-HS-glycoprotein (AHSG) and PDK4, two genes implicated in insulin resistance, were also highly expressed in SNEB. These results suggest that cows in SNEB experience alterations to the IGF and insulin signalling pathways in the postpartum endometrium. This may affect the rate of tissue repair with a possible negative impact on subsequent fertility.
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Larina, V. N., i V. I. Lunev. "The prognostic role of the index of global left ventricular function and its companion in patients with chronic heart failure and diabetes mellitus". FOCUS. Endocrinology 5, nr 2 (13.05.2024): 6–11. http://dx.doi.org/10.62751/2713-0177-2024-5-2-11.
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The index of global left ventricular function (LV IGF) is an imaging marker with pronounced prognostic properties in relation to the development of adverse cardiovascular events and death, determined on the basis of data from both magnetic resonance imaging (MRI) of the heart and echocardiographic examination (EchoCG). Companion indicator (companion) LV IGF (LV IGFC) is a marker obtained from the average quadratic value of the sum of the impact and global LV volume, designed to overcome the limitations of LV IGF due to its calculation formula.The aim. To evaluate the prognostic significance of LV IGF and its companion in patients aged 60 years and older with CHF and type 2 diabetes mellitus observed in outpatient settings.Material and methods. The study included 215 outpatient patients: 110 (51.2%) men and 105 (48.8%) women aged 72 (67; 78) years with CHF IIa–III stage II–IV FC. And LVH (in %) was calculated using the formula: EG LV = (KDO LV–CSR LV)/[0.5=(UP TO LV+CSR LV)+(MMLJ/1.05)]=100. IGFC LJ = {(KDO LJ-CSR LJ)2+[0.5×(BDO LJ+CSR LJ)+(MMLJ/1.05)]2}0.5. The duration of the observation period was 29 (20; 36) months.Results. LV IGF as a whole amounted to 20.6 (16.9; 23.2)%. LV IGF as a whole amounted to 313.8 (262.8; 400.0) ml. Depending on the presence or absence of DM, patients were divided into two groups: 68 patients with DM (group 1); 147 patients without DM (group 2). During the follow–up period of 29 (20; 36) months, 122 (56.7%) patients were hospitalized: in group 1–32 out of 68 (47.1%) patients; in group 2–90 out of 147 (61.2%) patients. The threshold value of LV IGF for predicting hospitalization due to CVD decompensation in group 1 patients was 21.4% or lower (area under the curve [PPK] 0.677±0.065, 95% CI 0.549–0.805, p=0.012; sensitivity 68.8%, specificity 61.1%); LV IGFC – 300.3 ml or more (PPK 0.666±0.067, 95% CI 0.535–0.797, p=0.019; sensitivity 62.5%, specificity 61.1%). There was a high rate of hospitalization due to CVD decompensation in group 1 with LV IGF of 21.4% or less (among patients with LV IGF of ≤21.4%, 59.5% of patients were hospitalized, more than 21.4% –32.3%) (OR 3.08, p<0.05); with LV IGFC of 300.3 ml or more (among patients with LV IGFC ≥300.3 ml, 58.8% of patients were hospitalized, less than 300.3 ml – 35.3%) (OR 2.62, p>0.05).Conclusion. The threshold value of LV IGF for predicting decompensation of cardiovascular disease with subsequent hospitalization in patients 60 years and older with CHF and DM was ≤21.4%; LV IGF was ≥300.3 ml. The data obtained allow us to consider LV IGF, LV IGFC, as well as their combination as markers of an unfavorable prognosis in older patients with CHF and DM at the outpatient stage.
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Jiang, Sheng, i Jing Yang. "Association of insulin-like growth factor-1 and insulin-like growth factor-binding protein-3 with estimated glomerular filtration rate in patients with type 2 diabetes mellitus". Global Translational Medicine 1, nr 2 (21.09.2022): 62. http://dx.doi.org/10.36922/gtm.v1i2.62.
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Type 2 diabetes mellitus patients often suffer from kidney damage, which is more serious than in ordinary people. The insulin-like growth factor (IGF) system has synergistic effects with other hormonal axes and has an essential role in glucose metabolism and type 2 diabetes. The study aimed to observe the association of IGF-1 and IGF factor-binding protein-3 (IGFBP-3) with estimated glomerular filtration rate (eGFR) in patients with type 2 diabetes mellitus. We recruited 521 patients with type 2 diabetes from the Endocrinology Department of the First Affiliated Hospital of Xinjiang Medical University from March 1, 2021, to December 20, 2021. The clinical data we collected were analyzed to determine the association of IGF-1 and IGFBP-3 with eGFR in patients with type 2 diabetes. Spearman correlation analysis showed that eGFR was positively correlated with IGF-1 and IGFBP-3 in all subjects (P = 0.044 and P = 0.004, respectively). We developed a linear regression model. In the multiple linear regression model, serum IGF-1 and IGFBP-3 were positively correlated with eGFR (β = 0.03, 95% CI = 0.01 – 0.06; P = 0.009 and β = 1.29, 95% CI = 0.09 – 2.49; P = 0.035). The results of the correlations were further validated. This preliminary study demonstrated positive associations of serum IGF-1 and IGFBP-3 levels with eGFR in patients with type 2 diabetes.
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Tally, Michael, Choh Hao Li i Kerstin Hall. "IGF-2 stimulated growth mediated by the somatomedin type 2 receptor". Biochemical and Biophysical Research Communications 148, nr 2 (październik 1987): 811–16. http://dx.doi.org/10.1016/0006-291x(87)90948-x.
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Westwood, M. "THE IGF AXIS AT THE FETO-MATERNAL INTERFACE". Reproductive Medicine Review 9, nr 3 (październik 2001): 173–96. http://dx.doi.org/10.1017/s096227990100031x.
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The insulin-like growth factors IGF-I and -II have effects on metabolism, growth, proliferation and differentiation in many tissues and cell types and are therefore important modulators of multiple aspects of physiology. IGF actions are largely mediated via the type 1 IGF receptor, though both peptides, particularly IGF-II, can bind to a second receptor known as the type 2 IGF/mannose-6-phosphate receptor. Access to these receptors is controlled by a family of six highly specific binding proteins (IGFBPs 1–6). Originally, the IGFBPs were thought of as IGF inhibitors, since their affinity for ligand is substantially higher than that of the receptors. More recently however, it has become apparent that modification of the binding proteins, for example proteolyis, phosphorylation or association with extracellular matrix, can influence IGFBP affinity for IGF and therefore IGF bioavailability and function.
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Munoz, A., P. Trigo, C. Riber, V. Malonda i F. Castejon. "A study of serum insulin-like growth factor type 1 (IGF-1) concentrations in resting untrained Andalusian horses: influence of age and gender". Veterinární Medicína 56, No. 5 (10.06.2011): 231–42. http://dx.doi.org/10.17221/1562-vetmed.
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Growth rate, tissue repair and reproductive functions are mediated by the somatotrophic axis, the growth hormone (GH) being one of its main components. GH is released in a pulsatile manner and a single measurement does not provide accurate information on the activity of the somatotrophic axis. The actions of GH on tissues are mediated by insulin-like growth factor type 1 (IGF-1), mainly released by the liver, and thus, the measurement of IGF-1 could be considered a good indicator of the activity of GH and the somatotrophic axis. Serum IGF-1 concentrations are relatively stable due to its long biological half-life without obvious diurnal rhythm. Additionally, many diseases significantly alter circulating IGF-1 concentrations, leading to potential diagnostic and prognostic uses in veterinary medicine. However, serum IGF-1 concentrations are affected by many factors, such as breed, age and sex. The present study analyzes the influence of these factors on serum IGF-1 concentrations in a population of 255 Andalusian horses (141 females and 114 males), divided into age groups: 1–2, 2–3, 3–4, 4–5, 5–6 and 6–12 months and 1–2, 2–4, 4–6, 6–10 and 10–14 years. The animals belonged to six different farms located in the same geographic location and were subjected to similar feeding and management protocols. Two measurements of body size were made: height at the withers (HW) and diameter of the thorax (DTx). Blood samples were taken always in the morning, in the month of July and serum IGF-1 concentrations were measured with a sandwich ELISA after dissociation of IGF-1 from its binding proteins. It was found that age and sex significantly influenced serum IGF-1 concentrations, whereas the effects of the farm and the time of blood withdrawal were not significant. Mean serum concentrations for both males and females respectively were: 246.3 and 231.0 (1–2 months), 201.9 and 194.7 (2–3 months), 174.2 and 170.4 (3–4 months), 161.7 and 155.4 (4–5 months), 166.1 and 136.9 (5–6 months), 127.2–114.5 (6–12 months), 103.3 and 89.01 (1–2 years), 104.3 and 73.41 (2–4 years), 105.4 and 64.40 (4–6 years), 53.29 and 68.27 (6–10 years) and 59.56 and 65.53 ng/ml (10–14 years). A progressive decrease in serum IGF-1 concentrations with increased age was found for both sexes. Males aged between five and 12 months and between two and six years had significantly higher serum IGF-1 concentrations than females of the same age. Coefficients of correlation between the indicators of body size (HW and DTx) and IGF-1 were –0.800 and –0.690 for the whole population of Andalusian horses, –0.860 and –0.750 for the males and –0.740 and –630 for the females. It is concluded that serum IGF-1 concentrations in Andalusian horses are reduced with ageing, male horses of determined age groups had higher IGF-1 than the females and there are negative correlations between body size and IGF-1 concentrations. The knowledge of the normal serum IGF-1 concentrations will help us to understand the role of the somatotrophic axis in several diseases and physiological situations and will provide information for further research on this equine breed.
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Braulke, T. "Type-2 IGF Receptor: A Multi-Ligand Binding Protein". Hormone and Metabolic Research 31, nr 02/03 (styczeń 1999): 242–46. http://dx.doi.org/10.1055/s-2007-978725.
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Simpson, Aaron D., Ying Wei Jenetta Soo, Guillaume Rieunier, Tamara Aleksic, Olaf Ansorge, Chris Jones i Valentine M. Macaulay. "Type 1 IGF receptor associates with adverse outcome and cellular radioresistance in paediatric high-grade glioma". British Journal of Cancer 122, nr 5 (20.12.2019): 624–29. http://dx.doi.org/10.1038/s41416-019-0677-1.
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AbstractHigh-grade glioma (HGG) is highly resistant to therapy, prompting us to investigate the contribution of insulin-like growth factor receptor (IGF-1R), linked with radioresistance in other cancers. IGF-1R immunohistochemistry in 305 adult HGG (aHGG) and 103 paediatric/young adult HGG (pHGG) cases revealed significant association with adverse survival in pHGG, with median survival of 13.5 vs 29 months for pHGGs with moderate/strong vs negative/weak IGF-1R (p = 0.011). Secondly, we tested IGF-1R inhibitor BMS-754807 in HGG cells, finding minimal radiosensitisation of 2/3 aHGG cell lines (dose enhancement ratios DERs < 1.60 at 2–8 Gy), and greater radiosensitisation of 2/2 pHGG cell lines (DERs ≤ 4.16). BMS-754807 did not influence radiation-induced apoptosis but perturbed the DNA damage response with altered induction/resolution of γH2AX, 53BP1 and RAD51 foci. These data indicate that IGF-1R promotes radioresistance in pHGG, potentially contributing to the association of IGF-1R with adverse outcome and suggesting IGF-1R as a candidate treatment target in pHGG.
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Oguchi, S., W. A. Walker i I. R. Sanderson. "Differentiation and Polarity Alter the Binding of IGF‐I to Human Intestinal Epithelial (Caco‐2) Cells". Journal of Pediatric Gastroenterology and Nutrition 20, nr 2 (luty 1995): 148–55. http://dx.doi.org/10.1002/j.1536-4801.1995.tb11527.x.
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SummaryThis study examined whether insulin‐like growth factor‐I (IGF‐I) bound to specific functioning IGF receptors on the surface of Caco‐2 cells and how this binding was affected by the differentiation and polarity of these cells. IGF‐I, which increased cell proliferation in a dose‐dependent manner, bound to a specific receptor on the surface of Caco‐2 cells. Affinity cross‐linking with labeled IGF‐I followed by reducing sodium dodecylsul‐fate‐polyacrylamide gel electrophoresis (SDS‐PAGE) showed Mrs at 135,000, 270,000 and 355,000 bands, which was inhibited by unlabeled IGF‐I. A Scatchard analysis of radioligand‐receptor binding showed the presence of a single class of receptors with high affinity for IGF‐I. This class of receptors was specific for IGF‐I, the affinity of IGF‐I to the receptor being four and 150 times greater than IGF‐II and insulin, respectively. There was no difference in the affinity of IGF‐I to type 1 IGF receptors between less‐differentiated [dissociation constant (Kd) = 3.81 nM] and well‐differentiated cells (Kd = 3.78 nM); however, well‐differentiated cells showed a 2.4‐fold higher maximum number of binding sites (Bmax) than less‐differentiated cells (3.45 vs. 1.44 x 104 sites/cell), indicating an increase in the density of IGF‐I receptors with differentiation. Furthermore, the number of type 1 IGF receptors on the basolateral surface of well‐differentiated cells was 2.4 times greater than that seen on the apical surface. In summary, IGF‐I binds to a single class of specific Caco‐2 cell‐surface receptors, which increase in number with differentiation and are found on both aspects of the epithelium.
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Solarek, W., A. M. Czarnecka, B. Escudier, Z. F. Bielecka, F. Lian i C. Szczylik. "Insulin and IGFs in renal cancer risk and progression". Endocrine-Related Cancer 22, nr 5 (październik 2015): R253—R264. http://dx.doi.org/10.1530/erc-15-0135.
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Insulin and IGFs play a significant role in cancer development and progression, including renal cell carcinoma (RCC). RCC is the most frequent type of kidney cancer in adults and the tenth most common malignancy worldwide. Insulin is normally associated with metabolism control, whereas IGFs are defined as proliferation regulators. Today, there is convincing evidence of an association between obesity and the risk of RCC. Indicated risk factors together with type 2 diabetes are irreversibly connected with circulating insulin and IGF levels. The interplay between these molecules, their receptors, and IGF-binding proteins might be crucial for RCC cell biology and RCC progression. Given the potent activity IGF/IGF receptor 1 (IGF1R) inhibitors demonstrate against RCC in basic research, some type of combination therapy may prove to be beneficial clinically in the management of RCC. This review addresses not only molecular but also clinical associations between insulin and IGF1 signaling pathways and both RCC biology and clinical course. Revealing these interactions may improve our understanding of basic molecular oncology processes in RCC and improve treatment strategies.
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Huynh, HoangDinh, Junke Zheng i Chengcheng Zhang. "IGF Binding Protein 2 Supports the Cycling of Hematopoietic Stem Cells." Blood 116, nr 21 (19.11.2010): 1604. http://dx.doi.org/10.1182/blood.v116.21.1604.1604.
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Abstract Abstract 1604 Previously we identified IGFBP2 as an extrinsic factor that supports ex vivo expansion of hematopoietic stem cells (HSCs). The role of IGFBP2 in HSCs and cancer is very intriguing. IGFBP2 can bind to insulin-like growth factor (IGF) ligands and displays IGF-dependent growth inhibitory effects on many cell types. On the other hand, IGFBP2 is capable of stimulating growth of certain cancer cells, and is overexpressed in many cancer patients and its expression is correlated with cancer progression. Here we sought to study the role of IGFBP2 in regulation of the activity of normal HSCs. We showed that IGFBP2 was expressed in differentiated hematopoietic cells and bone marrow stroma but not in HSCs. Consistent with its gene expression pattern, IGFBP2-/- HSCs had similar repopulation activity as their wild-type counterparts. By contrast, when we transplanted HSCs into IGFBP2-/- or wild-type recipient mice, we found decreased in vivo repopulation of HSCs in primary and secondary transplanted IGFBP2-/- recipients, suggesting that the environmental IGFBP2 positively supports HSC activity. Further co-culture of HSCs with IGFBP2-/- or wild-type bone marrow stromal cells indicated that IGFBP2 produced by bone marrow stroma indeed supports HSC expansion. Consistently, HSCs in IGFBP2-/- mice showed decreased frequency and cell cycling, and had upregulated expression of cell cycle inhibitors of p21, p16, and p19. To determine whether IGFBP2's effect on HSCs depends on IGF signaling, we compared the repopulation of donor cells deficient for the IGF type I receptor in wild-type and IGFBP2-/- recipients. These HSCs that are defective in IGF signaling still have decreased repopulation in IGFBP2-/- recipients, suggesting that the environmental effect of IGFBP2 on HSCs is independent of IGF signaling. To identify the functional domain of IGFBP2 in regulation of HSC activity, we constructed IGFBP2 with mutated RGD domain or deleted c-terminus and used the mutant IGFBP2 proteins in ex vivo culture of HSCs. We found that the c-terminus of IGFBP2 is essential to support HSC activity. We are currently in the process of identifying the potential receptor of IGFBP2 on HSCs. In summary, we found that IGFBP2 supports the cycling of normal HSCs, and this effect is independent of IGF signaling. Our study is important in revealing the relationship among environmental cues and cell fates of stem cells and opens up a new avenue in investigation of the roles of IGFBP2 in stem cells and cancer. Disclosures: No relevant conflicts of interest to declare.
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Geenen, Vincent, i Olivier Dardenne. "Thymus Dysfunction in the Development of Type 1 Diabetes and Endocrine Autoimmune Diseases". European Endocrinology 05 (2009): 24. http://dx.doi.org/10.17925/ee.2009.05.00.24.
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The discovery that thymic epithelium from many species expresses a large repertoire of genes encoding neuroendocrine and other tissuerestricted antigens has radically changed our knowledge of the pathogenic mechanisms underlying the development of organ-specific autoimmune diseases such as type 1 diabetes and autoimmune endocrine diseases. Rather than a breakdown of immunological selftolerance in periphery, there is mounting evidence that the diabetogenic autoimmune response may first arise from a thymus dysfunction in the central programming of β-cell self-tolerance. Insulin-like growth factor 2 (IGF-2) is the dominant member of the insulin gene/protein family expressed in thymic epithelial cells (TECs) from different species, and Igf2-/- mice fail to programme complete tolerance to insulin. Based on the homology between insulin, the primary and immunogenic auto-antigen of type 1 diabetes, and IGF-2, the tolerogenic selfantigen of the insulin family, the design of a regulatory/negative self-vaccination for prevention against type 1 diabetes has been proposed and is under development.
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Zhang, Donglei, Menashe Bar-Eli, Sylvain Meloche i Pnina Brodt. "Dual Regulation of MMP-2 Expression by the Type 1 Insulin-like Growth Factor Receptor". Journal of Biological Chemistry 279, nr 19 (1.03.2004): 19683–90. http://dx.doi.org/10.1074/jbc.m313145200.
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The matrix metalloproteinase (MMP)-2 has been recognized as a major mediator of basement membrane degradation, angiogenesis, tumor invasion, and metastasis. The factors that regulate its expression have not, however, been fully elucidated. We previously identified the type I insulin-like growth factor (IGF-I) receptor as a regulator of MMP-2 synthesis. The objective of the present study was to investigate the signal transduction pathway(s) mediating this regulation. We show here that in Lewis lung carcinoma subline H-59 cells treated with IGF-I (10 ng/ml), the PI 3-kinase (phosphatidylinositol 3′-kinase) /protein kinase B (Akt) and C-Raf/ERK pathways were activated, andMMP-2promoter activity, mRNA, and protein synthesis were induced. MMP-2 induction was blocked by the PI 3-kinase inhibitors LY294002 and wortmannin, by overexpression of a dominant-negative Akt or wild-type PTEN (phosphatase and tensin homologue deleted on chromosome 10), and by rapamycin. In contrast, a MEK inhibitor PD98059 failed to reduceMMP-2promoter activation and actually increasedMMP-2mRNA and protein synthesis by up to 30%. Interestingly, suppression of PI 3-kinase signaling by a dominant-negative Akt enhanced ERK activity in cells stimulated with 10 ng/ml but not with 100 ng/ml IGF-I. Furthermore, at the higher (100 ng/ml) IGF-I concentration, C-Raf and ERK, but not PI 3-kinase activation, was enhanced, and this resulted in down-regulation of MMP-2 synthesis. This effect was reversed in cells expressing a dominant-negative ERK mutant. The results suggest that IGF-I can up-regulate MMP-2 synthesis via PI 3-kinase/Akt/mTOR (the mammalian target of rapamycin) signaling while concomitantly transmitting a negative regulatory signal via the Raf/ERK pathway. The outcome of IGF-IR (the receptor for IGF-I) activation may ultimately depend on factors, such as ligand bioavailability, that can shift the balance preferentially toward one pathway or the other.
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van Neck, J. W., A. Flyvbjerg, A. G. P. Schuller, R. R. Rosato, C. Groffen, M. van Kleffens, D. Lindenbergh-Kortleve, I. Dørup i S. L. S. Drop. "IGF, type I IGF receptor and IGF-binding protein mRNA expression in kidney and liver of potassium-depleted and normal rats infused with IGF-I". Journal of Molecular Endocrinology 19, nr 1 (sierpień 1997): 59–66. http://dx.doi.org/10.1677/jme.0.0190059.
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ABSTRACT Dietary potassium (K) depletion is known to reduce body weight gain and organ growth, except for kidney which increases in weight. This renal hypertrophy is preceded by increased renal IGF-I levels. In the present study, we investigated IGF-I and -II, type I IGF receptor and IGF-binding protein (IGFBP) mRNA expression in liver and kidney of K-depleted and normal rats infused with vehicle or recombinant human IGF-I. Body weight gain was almost completely arrested in K-depleted rats without any stimulatory effect of IGF-I infusion. Both absolute and relative kidney weight (kidney weight/body weight) were significantly increased in K-depleted rats and this was further enhanced by IGF-I infusion. In contrast, relative liver weight was comparable in the different groups and unaffected by IGF-I infusion. IGF-I mRNA expression was significantly lower in kidney and liver of K-depleted animals whereas type I IGF receptor levels were unchanged. In contrast, in kidney, K depletion increased IGFBP-1 and -2 mRNA expression with no additional effect of IGF-I infusion. In liver of K-depleted animals, IGFBP-1 mRNA expression was increased whereas increased IGFBP-1 and -2 mRNA expression was observed when these animals were infused with IGF-I. These observations may point towards a differential mode of action of the IGFBPs. In kidney increased IGFBP-1 and -2 mRNA expression may enhance IGF-I bioavailability with subsequent kidney growth. In liver, with clearly detectable type I IGF receptor mRNA expression, increased IGFBP levels may protect from IGF-I-induced organ growth by decreasing IGF-I bioavailability.
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Parker, E. A., A. Hegde, M. Buckley, K. M. Barnes, J. Baron i O. Nilsson. "Spatial and temporal regulation of GH–IGF-related gene expression in growth plate cartilage". Journal of Endocrinology 194, nr 1 (lipiec 2007): 31–40. http://dx.doi.org/10.1677/joe-07-0012.
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Previous studies of the GH–IGF system gene expression in growth plate using immunohistochemistry and in situ hybridization have yielded conflicting results. We therefore studied the spatial and temporal patterns of mRNA expression of the GH–IGF system in the rat proximal tibial growth plate quantitatively. Growth plates were microdissected into individual zones. RNA was extracted, reverse transcribed and analyzed by real-time PCR. In 1-week-old animals, IGF-I mRNA expression was minimal in growth plate compared with perichondrium, metaphyseal bone, muscle, and liver (70-, 130-, 215-, and 400-fold less). In contrast, IGF-II mRNA was expressed at higher levels than in bone and liver (65- and 2-fold). IGF-II expression was higher in the proliferative and resting zones compared with the hypertrophic zone (P < 0.001). GH receptor and type 1 and 2 IGF receptors were expressed throughout the growth plate. Expression of IGF-binding proteins (IGFBPs)-1 through -6 mRNA was low throughout the growth plate compared with perichondrium and bone. With increasing age (3-, 6-, 9-, and 12-week castrated rats), IGF-I mRNA levels increased in the proliferative zone (PZ) but remained at least tenfold lower than levels in perichondrium and bone. IGF-II mRNA decreased dramatically in PZ (780-fold; P < 0.001) whereas, type 2 IGF receptor and IGFBP-1, IGFBP-2, IGFBP-3, and IGFBP-4 increased significantly with age in growth plate and/or surrounding perichondrium and bone. These data suggest that IGF-I protein in the growth plate is not produced primarily by the chondrocytes themselves. Instead, it derives from surrounding perichondrium and bone. In addition, the decrease in growth velocity that occurs with age may be caused, in part, by decreasing expression of IGF-II and increasing expression of type 2 IGF receptor and multiple IGFBPs.
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Reynaud, Karine, Sylvie Chastant-Maillard, Séverine Batard, Sandra Thoumire i Philippe Monget. "IGF system and ovarian folliculogenesis in dog breeds of various sizes: is there a link?" Journal of Endocrinology 206, nr 1 (20.04.2010): 85–92. http://dx.doi.org/10.1677/joe-09-0450.
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The IGF system plays a crucial role in ovarian folliculogenesis, and changes in IGF-binding protein (IGFBP) levels modulate IGF bioavailability. Data from various mammalian models suggest a link between body size, IGF1 in serum and female reproduction parameters. Among the vertebrate species, the dog exhibits the widest span in body height. Height is known to be positively correlated with the concentration of serum IGF1. In this work, the ovarian physiology of 40 bitches exhibiting a wide span of height, and breed type was investigated. IGF1, IGF2, IGFBP3, estradiol (E2), and progesterone concentrations in plasma and preovulatory follicular fluid were quantified. A total of 455 follicles, 2–8 mm in diameter, were recovered at the preovulatory stage, measured, and punctured. Intrafollicular levels of IGF1 were positively correlated with plasma levels, and plasma IGF1 levels were positively correlated with both bitch height and weight. The concentrations were threefold higher in large dogs compared with small dogs. A positive correlation between intrafollicular and plasmatic IGFBP3 levels and a positive correlation between plasmatic IGFBP3 levels, and both height and weight of the bitches were observed. The number of preovulatory follicles and the diameter of the three largest follicles were positively correlated with bitch height. E2 intrafollicular concentrations were higher in preovulatory follicles from small animals than in those from large animals. In conclusion, the strong variability in height between dogs appeared to be associated with dramatic differences in IGF1, and IGFBP3 levels, in both plasma and follicular fluid. These differences were associated with significant differences in some functional aspects of ovarian follicles.
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Chahar, Deeksha, Gyanendra Kumar Sonkar, Sangeeta Singh, Satyendra Kumar Sonkar i Mohammad Kaleem Ahmad. "Unraveling Epigenetic Signatures for Early Detection of Diabetes Nephropathy in Type 2 Diabetes: A Case–Control Investigation". Biomedical and Biotechnology Research Journal 8, nr 1 (2024): 108–16. http://dx.doi.org/10.4103/bbrj.bbrj_289_23.
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Background: Type 2 diabetes mellitus (T2DM) leads to a substantial elevation in the occurrence of various micro- and macrovascular complications. Approximately one-third of patients of both type 1 diabetes and T2DM develop diabetes nephropathy (DN). Emerging findings in epigenetic modifications indicate that differences in DNA methylation patterns could have a more substantial impact when assessing the susceptibility to type 2 diabetes mellitus (T2DM) in contrast to genetic variations. Methods: The study involved 298 participants, encompassing 75 individuals with type 2 diabetes mellitus (T2DM), 74 individuals with diabetes nephropathy (DN), and 149 healthy control subjects aged between 20 and 70 years. The concentrations of circulating adiponectin, insulin-like growth factor (IGF) 1, and IGF2 were quantified using enzyme-linked immunoassay. The amount of RNA in each sample (control, T2DM, and DN) was quantified, and its purity was checked using nanodrop. Real-time analysis of Adiponectin, IGF1, IGF2, and GAPDH genes was conducted using the SYBR Green polymerase chain reaction Master Mix assay. Results: Circulating levels of IGF1 level were significantly lower in both T2DM and DN, whereas it was slightly higher in T2DM than the DN. IGF2 circulating level was higher in both T2DM and DN as compared to control, whereas it was lower in T2DM when compared to DN. The gene expression level of adiponectin was reduced in both T2DM and DN when compared to the control group; however, it was higher in T2DM than in DN. The gene expression level of IGF1 was decreased in both T2DM and DN compared to the control group, with a more significant decrease in DN compared to T2DM. Conclusion: The measurement of circulatory levels of adiponectin, IGF1, and IGF2 in serum, along with gene expression analysis, provides valuable insights for predicting the progression from T2DM to DN. Consequently, these markers hold the potential to enhance early diagnosis, guide treatment strategies, and serve as innovative prognostic indicators for DN diagnosis.
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Shooter, G. K., B. Magee, M. A. Soos, G. L. Francis, K. Siddle i J. C. Wallace. "Insulin-like growth factor (IGF)-I A- and B-domain analogues with altered type 1 IGF and insulin receptor binding specificities". Journal of Molecular Endocrinology 17, nr 3 (grudzień 1996): 237–46. http://dx.doi.org/10.1677/jme.0.0170237.
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ABSTRACT Insulin-like growth factor-I (IGF-I) analogues were produced with the aim of identifying IGF-I residues that contribute to the specificity of binding to the type 1 IGF receptor as opposed to the insulin receptor. Receptor binding properties of a series of A- and B-domain analogues were compared using rat L6 myoblasts, soluble human IGF type 1 receptors and soluble human insulin receptor isoforms HIR-A (−Ex11) and HIR-B (+Ex11). IGF-I analogues, [Leu8] IGF-I and [Phe59] IGF-I, were shown to exhibit respectively, a 28- and 17-fold decrease in affinity for the HIR-A with only a 6- and 5-fold decrease in affinity for the human IGF type 1 receptor. In contrast, the analogue [His4] IGF-I was equipotent to IGF-I in binding to the soluble type 1 IGF receptor while showing 7-fold and 4-fold increases in HIR-A and HIR-B binding respectively. Furthermore, [Leu62] IGF-I was 8-fold less potent than IGF-I in soluble IGF type 1 receptor binding but only showed a 2-fold decrease in HIR-A and HIR-B binding. Our study supports the conclusion that the co-evolution of the IGF-I and insulin receptor/ligand systems has resulted in subtle structural differences in the A- and B-regions of each ligand important for defining receptor binding specificity.
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Yazdanpanah, Mojgan, Fakhredin A. Sayed-Tabatabaei, Joop A. M. J. L. Janssen, Ingrid Rietveld, Albert Hofman, Theo Stijnen, Huibert A. P. Pols, Steven W. J. Lamberts, Jacqueline C. M. Witteman i Cornelia M. van Duijn. "IGF-I gene promoter polymorphism is a predictor of survival after myocardial infarction in patients with type 2 diabetes". European Journal of Endocrinology 155, nr 5 (listopad 2006): 751–56. http://dx.doi.org/10.1530/eje.1.02276.
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Objective: Previously we observed that non-carriers of the most common alleles of an IGF-I promoter polymorphism have low circulating IGF-I levels and an increased risk of developing myocardial infarction (MI), particularly in patients with type 2 diabetes. Design: We investigated whether this IGF-I promoter polymorphism is associated with survival of type 2 diabetes in a Caucasian population aged 55 years and older. Methods: The study was embedded in the Rotterdam Study, a prospective population-based cohort study. At baseline, 668 patients with type 2 diabetes were diagnosed, among which, 55 incident MI were ascertained during follow-up. For the present study, we used two genotype groups: non-variant carriers (homozygous for 192, 194, or 192/194 bp genotypes), and variant carriers. Results: During a median follow-up of 8.8 years, 396 out of the 668 patients with type 2 diabetes (59.3%) died of various causes. The frequency of type 2 diabetes variant carrier and non-variant carriers was 28.7 and 71.3% respectively. The survival in patients with type 2 diabetes without an MI did not differ between the IGF-I genotype groups (hazard ratio (HR) = 0.8, 95% confidence interval (CI): 0.7–1.1, P = 0.1). In contrast, in those who developed an MI, variant carriers had a 2.4 times higher risk of mortality than non-variant carriers (95% CI: 1.2–4.8, P = 0.01). Conclusion: Our study suggests that genetically determined low IGF-I activity is an important determinant of survival in patients with type 2 diabetes who developed an MI. The IGF-I promoter polymorphism, therefore, may help to predict the future mortality risk in this group of patients.
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Batchelor, D. C., A.-M. Hutchins, M. Klempt i S. J. M. Skinner. "Developmental changes in the expression patterns of IGFs, type 1 IGF receptor and IGF-binding proteins-2 and -4 in perinatal rat lung". Journal of Molecular Endocrinology 15, nr 2 (październik 1995): 105–15. http://dx.doi.org/10.1677/jme.0.0150105.
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ABSTRACT The insulin-like growth factors (IGF-I and IGF-II), their receptors and binding proteins (IGFBPs) are endogenously expressed in a number of tissues including the lung during fetal and neonatal development. This endogenous autocrine/paracrine IGF 'system', together with endocrine sources, contributes to the regulation of lung cell proliferation. We investigated the expression of the mRNAs encoding IGF-I, IGF-II, the type 1 IGF receptor (IGF-T1R) and two IGF-binding proteins (IGFBP-2 and IGFBP-4) in rat lung during the perinatum. These were compared in lung with surfactant apoprotein A (Sp-A) mRNA levels. mRNA in extracts of fetal tissues collected between day 17 of gestation (17f) and day 9 after birth (9d) was estimated by Northern blot or RNase protection analysis. At day 20 of gestation IGF-I, IGF-T1R and IGFBP-4 mRNA levels were higher in lung than liver (all P<0·01), whereas IGF-II and IGFBP-2 mRNA levels were higher in liver than lung (each P<0·02). The expression of IGF-I, IGFBP-2 and IGFBP-4 in lung was high before birth (days 17–20f) but decreased to low levels at days 21f, 22f or at birth (1d) but increased in the neonatal lung. IGF-II expression in lung was high at 17f but decreased before birth and remained low after birth. The IGF-T1R was expressed at moderate levels before birth, decreased before birth but peaked at days 2–5 after birth. The decrease in expression of these growth regulators before birth was matched by an increase in Sp-A expression which was clearly seen at day 20f, peaked at 1d and then was maintained at high levels after birth. Primary cell cultures of 18f lung epithelia express IGFBP-2 while fibroblasts from the same animals express only IGFBP-4. Cells grown from 22f lung tissue express IGFBP-2 and IGFBP-4 at lower levels, behaving in vitro as they do in vivo. The contrasting levels of expression of different components of the IGF system in the fetal lung and liver indicate organ-specific regulation. IGFBP-2 and IGFBP-4 expression in different cell types within lung but with similar temporal changes suggests cell-specific regulation, perhaps by a common agent. The patterns of expression of IGF-I, IGF-T1R, IGFBP-2 and IGFBP-4, but not IGF-II, in developing lung correspond to previously described phasic changes in lung cell proliferation rates. The nadir in expression of these four major components of the lung IGF system occurs in the saccular phase when the lung begins to differentiate, probably under the influence of certain endocrine agents.
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Logie, A., N. Boulle, V. Gaston, L. Perin, P. Boudou, Y. Le Bouc i C. Gicquel. "Autocrine role of IGF-II in proliferation of human adrenocortical carcinoma NCI H295R cell line". Journal of Molecular Endocrinology 23, nr 1 (1.08.1999): 23–32. http://dx.doi.org/10.1677/jme.0.0230023.
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In adrenocortical tumors, the malignant phenotype is associated with rearrangements (paternal isodisomy) at the 11p15 locus and IGF-II gene overexpression, strongly suggesting that the IGF system is a major determinant of adrenocortical tumor progression. The aim of this study was to validate an in vitro model for investigating the involvement of the IGF system in adrenocortical tumorigenesis. We analyzed the production of IGF mRNA and proteins, IGF-binding proteins (IGFBPs) and IGF receptors by the NCI H295R cell line, which is derived from a human adult adrenocortical carcinoma. H295R cells were shown to proliferate for a long period (26 days) in the absence of serum or any added growth factor. Northern blot analyses showed high IGF-II mRNA contents in H295R cells. The cells secreted large amounts of IGF-II protein (14 ng/10(6) cells per 48 h) although no IGF-I protein was detected. Western ligand blot analyses of conditioned media detected the presence of large amounts of a 34 kDa protein, which was identified as IGFBP-2 by immunoblotting. The presence of high-affinity binding sites for IGF-I and IGF-II on H295R cells was shown by binding experiments using radiolabeled IGFs and confirmed by reverse transcription PCR analyses showing type 1 and type 2 IGF receptors. Proliferation of H295R cells was inhibited by anti-IGF-II antibody (45%) and by anti-type 1 IGF receptor antibody (53%) indicating that IGF-II is an autocrine growth factor for these cells and that its effects are, at least in part, mediated by the type 1 IGF receptor. These findings confirm the involvement of the IGF system in adrenocortical tumors and suggest that the H295R cell line is a suitable in vitro model for studying the molecular mechanisms of adrenocortical tumor proliferation.
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Smink, JJ, JA Koedam, JG Koster i SC van Buul-Offers. "Dexamethasone-induced growth inhibition of porcine growth plate chondrocytes is accompanied by changes in levels of IGF axis components". Journal of Endocrinology 174, nr 2 (1.08.2002): 343–52. http://dx.doi.org/10.1677/joe.0.1740343.
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High (pharmacological) doses of glucocorticoids inhibit the proliferation of growth plate chondrocytes, which leads to one of the side-effects of these steroids, namely suppression of longitudinal growth. Growth inhibition by glucocorticoids is thought to be mediated in part by impaired action of components of the IGF axis, which are important for chondrocyte regulation and hence for longitudinal growth. The aim of the present study was to determine whether glucocorticoid-induced growth retardation involves changes in IGF axis components. Chondrocytes were isolated from epiphyseal growth plates of neonatal piglets and treated with pharmacological doses of dexamethasone (DXM) for 24 h to study glucocorticoid-induced growth retardation. Under IGF-I-supplemented (10 nM) culture conditions, IGF-binding proteins (IGFBPs)-2, -4 and -5 were secreted by the growth plate chondrocytes and IGFBP-2 protein and mRNA levels were decreased by the DXM treatment, whereas IGFBP-4 and -5 were not affected. Proliferation of the chondrocytes, as measured by [(3)H]thymidine incorporation, was 3.5-fold higher in serum-supplemented medium in contrast to IGF-I-supplemented (10 nM) medium. In the presence of serum, DNA synthesis was significantly inhibited by 50-63% when treated with 100 nM DXM, which was prevented by the glucocorticoid-receptor antagonist Org34116. mRNA levels of IGF axis components were determined using Northern blot analysis. IGFBP-2 to -6 were expressed in the chondrocytes, IGFBP-1 was absent and both IGF-I and IGF-II, and the type I and type II IGF receptors were expressed. Treatment with DXM (100 nM) resulted in a 2-fold increase in mRNA levels of both IGFBP-5 and the type I IGF receptor, whereas IGFBP-2 mRNA levels decreased by 55%, in concert with the decrease in protein level observed under IGF-I-supplemented culture conditions. The changes in mRNA levels due to the DXM treatment were prevented by the glucocorticoid receptor antagonist. Our data show that exposure to pharmacological doses of DXM results in inhibition of proliferation and changes in components of the IGF axis, IGFBP-2 and -5 and the type I IGF receptor, suggesting a role for these components in glucocorticoid-induced growth retardation at the local level of the growth plate.
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Biddle, C., C. H. Li, P. N. Schofield, V. E. Tate, B. Hopkins, W. Engstrom, N. S. Huskisson i C. F. Graham. "Insulin-like growth factors and the multiplication of Tera-2, a human teratoma-derived cell line". Journal of Cell Science 90, nr 3 (1.07.1988): 475–84. http://dx.doi.org/10.1242/jcs.90.3.475.
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A human teratoma cell line (Tera-2) was grown in serum-free medium, and the population multiplication was stimulated by the addition of somatomedins/insulin-like growth factors (IGFs). Both IGF-I and IGF-II gave maximal stimulation when added daily at 10 ng ml-1. The IGFs did not substantially change the labelling index of the cells, and the IGFs appeared to exert their effect on population multiplication by increasing cell survival. Membranes isolated from Tera-2 cells displayed both type 1 and type 2 IGF receptors.
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Lee, C. Y., F. W. Bazer i F. A. Simmen. "Expression of components of the insulin-like growth factor system in pig mammary glands and serum during pregnancy and pseudopregnancy: effects of oestrogen". Journal of Endocrinology 137, nr 3 (czerwiec 1993): 473–83. http://dx.doi.org/10.1677/joe.0.1370473.
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ABSTRACT To gain insight into the involvement and interactions of the insulin-like growth factors (IGFs) and oestrogen in mammary growth and differentiation, the temporal expression of mammary mRNAs encoding components of the IGF system in pregnant and pseudopregnant pigs was examined. Pseudopregnant pigs received 5 mg oestradiol valerate or vehicle daily from day 45 after oestrus and underwent mammary biopsy on days 60, 90 or 112. In mammary tissue of pregnant pigs, steady-state levels of the mRNAs encoding IGF-I, IGF-II and type-I IGF receptor as well as the levels of the membrane-associated type-II IGF receptor were higher during the early phase of mammogenesis (≤day 45) than during the subsequent stages of mammary development. Mammary IGF-I, IGF-II and type-I receptor mRNAs were expressed at their lowest levels around day 90 of pregnancy (20–40% of those for day 30 of pregnancy) coincident with the onset of β-casein mRNA accumulation. Mammary IGF-binding protein-2 (IGFBP-2) mRNA levels increased twofold during the latter half of pregnancy, whereas the amount of IGFBP-3 mRNA declined after day 30 to undetectable levels by midpregnancy. Pseudopregnant pigs had reduced levels of these mRNAs (except for IGF-II) relative to their pregnant counterparts and this was associated with premature differentiation of mammary tissue as reflected by an earlier onset of β-casein mRNA accumulation in the former. The administration of oestradiol valerate decreased the levels of IGF-I and type-I IGF receptor mRNAs by day 60 of pseudopregnancy, but the reverse was evident by day 112. Oestradiol administration increased β-casein mRNA levels in pseudopregnant pigs, but had no effect on mammary IGFBP-2 and IGFBP-3 mRNA levels. Mammary IGF content was greater in late pregnancy (≥day 90) and pseudopregnancy than at early pregnancy. Serum IGF-I and IGF-II levels declined steadily during pregnancy and this was similar to, but not correlated with, mammary IGF mRNA levels, whereas in pseudopregnant pigs, serum IGF concentrations did not change temporally or in response to oestradiol. Serum IGFBP-2 levels were unaltered during pregnancy or pseudopregnancy, but serum IGFBP-3 levels declined after day 60 of pregnancy. In pseudopregnant pigs, serum IGFBP-3 levels did not change temporally, but declined after oestradiol treatment. Results indicate that mammary IGF-I and type-I IGF receptor systems are down-regulated during pregnancy-associated differentiation of this tissue and in response to oestrogen. Locally produced (autocrine and paracrine) IGFs are likely to mediate mammogenesis, whereas oestrogen stimulates mammary differentiation and lactogenesis in the pig. However, the high mammary IGF content and the reciprocal expression of mammary IGFBP-2 and IGFBP-3 mRNAs during late pregnancy suggests the involvement of IGFs in lactogenesis as well. Journal of Endocrinology (1993) 137, 473–483
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Valverde, Angela M., Cecilia Mur, Michael Brownlee i Manuel Benito. "Susceptibility to Apoptosis in Insulin-like Growth Factor-I Receptor-deficient Brown Adipocytes". Molecular Biology of the Cell 15, nr 11 (listopad 2004): 5101–17. http://dx.doi.org/10.1091/mbc.e03-11-0853.
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Fetal brown adipocytes are insulin-like growth factor-I (IGF-I) target cells. To assess the importance of the IGF-I receptor (IGF-IR) in brown adipocytes during fetal life, we have generated immortalized brown adipocyte cell lines from the IGF-IR-/- mice. Using this experimental model, we demonstrate that the lack of IGF-IR in fetal brown adipocytes increased the susceptibility to apoptosis induced by serum withdrawal. Culture of cells in the absence of serum and growth factors produced rapid DNA fragmentation (4 h) in IGF-IR-/- brown adipocytes, compared with the wild type (16 h). Consequently, cell viability was decreased more rapidly in fetal brown adipocytes in the absence of IGF-IR. Furthermore, caspase-3 activity was induced much earlier in cells lacking IGF-IR. At the molecular level, IGF-IR deficiency in fetal brown adipocytes altered the balance of the expression of several proapoptotic (Bcl-xS and Bim) and antiapoptotic (Bcl-2 and Bcl-xL) members of the Bcl-2 family. This imbalance was irreversible even though in IGF-IR-reconstituted cells. Likewise, cytosolic cytochrome c levels increased rapidly in IGF-IR-deficient cells compared with the wild type. A rapid entry of Foxo1 into the nucleus accompanied by a rapid exit from the cytosol and an earlier activation of caspase-8 were observed in brown adipocytes lacking IGF-IR upon serum deprivation. Activation of caspase-8 was inhibited by 50% in both cell types by neutralizing anti-Fas-ligand antibody. Adenoviral infection of wild-type brown adipocytes with constitutively active Foxol (ADA) increased the expression of antiapoptotic genes, decreased Bcl-xL and induced caspase-8 and -3 activities, with the final outcome of DNA fragmentation. Up-regulation of uncoupling protein-1 (UCP-1) expression in IGF-IR-deficient cells by transduction with PGC-1α or UCP-1 ameliorated caspase-3 activation, thereby retarding apoptosis. Finally, insulin treatment prevented apoptosis in both cell types. However, the survival effect of insulin on IGF-IR-/- brown adipocytes was elicited even in the absence of phosphatidylinositol 3-kinase/Akt signaling. Thus, our results demonstrate for the first time the unique role of IGF-IR in maintaining the balance of death and survival in fetal brown adipocytes.
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Viswambharan, Hema, Nadira Y. Yuldasheva, Helen Imrie, Katherine Bridge, Natalie J. Haywood, Anna Skromna, Karen E. Hemmings i in. "Novel Paracrine Action of Endothelium Enhances Glucose Uptake in Muscle and Fat". Circulation Research 129, nr 7 (17.09.2021): 720–34. http://dx.doi.org/10.1161/circresaha.121.319517.
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Rationale: A hallmark of type 2 diabetes is insulin resistance, which leads to increased endothelial cell (EC) production of superoxide and a simultaneous reduction in the availability of the vasoprotective signaling radical NO. We recently demonstrated in preclinical models that type 2 diabetes simultaneously causes resistance to IGF-1 (insulin-like growth factor-1)–mediated glucose lowering and endothelial NO release. Objective: To examine the effect of insulin and IGF-1 resistance specifically in ECs in vivo. Methods and Results: We generated mice expressing mIGF-1Rs (mouse IGF-1 receptors), which form nonfunctioning hybrid receptors with native IRs (insulin receptors) and IGF-1R, directed to ECs under control of the Tie2 promoter-enhancer. Despite EC insulin and IGF-1 resistance, mIGFREO (mutant IGF-1R EC overexpressing) mice had enhanced insulin and IGF-1–mediated systemic glucose disposal, lower fasting free fatty acids, and triglycerides. In hyperinsulinemic-euglycemic clamp studies, mIGFREO had increased glucose disposal and increased glucose uptake into muscle and fat, in response to insulin. mIGFREO had increased Nox (NADPH oxidase)-4 expression due to reduced expression of the microRNA, miR-25. Consistent with increased Nox4, mIGFREO ECs generated increased hydrogen peroxide (H 2 O 2 ), with no increase in superoxide. Treatment with catalase—a H 2 O 2 dismutase—restored insulin tolerance to WT (wild type) levels in mIGFREO. Conclusions: Combined insulin and IGF-1 resistance restricted to the endothelium leads to a potentially favorable adaptation in contrast to pure insulin resistance, with increased Nox4-derived H 2 O 2 generation mediating enhanced whole-body insulin sensitivity.
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Soos, M. A., C. E. Field i K. Siddle. "Purified hybrid insulin/insulin-like growth factor-I receptors bind insulin-like growth factor-I, but not insulin, with high affinity". Biochemical Journal 290, nr 2 (1.03.1993): 419–26. http://dx.doi.org/10.1042/bj2900419.
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Hybrid insulin/insulin-like growth factor-I (IGF-I) receptors have previously been described in human placenta, but it has not been possible to study their properties in the presence of classical insulin receptors and type I IGF receptors. To facilitate the purification of hybrids, we produced an anti-peptide monoclonal antibody IGFR 1-2, directed against the C-terminal peptide of the type I IGF receptor beta-subunit. The antibody bound native human and rat type I IGF receptors, and reacted specifically with the beta-subunit on immunoblots. Solubilized placental microsomal membranes were depleted of classical type I IGF receptors by incubation with an immobilized monoclonal antibody IGFR 24-55, which reacts well with type I receptors but very poorly with hybrid receptors. Residual hybrid receptors were then isolated by incubation with immobilized antibody IGFR 1-2, and recovered by elution with excess of synthetic peptide antigen. Binding properties of hybrids were compared with those of immuno-affinity-purified insulin receptors and type I IGF receptors, by using the radioligands 125I-IGF-I and 125I-insulin. Hybrids bound approx. 20 times as much 125I-IGF-I as 125I-insulin at tracer concentrations (approx. 0.1 nM). The binding of 125I-insulin, but not 125I-IGF-I, to hybrids increased after treatment with dithiothreitol to reduce disulphide bonds between the alpha-subunits. Hybrids behaved very similarly to type I receptors with respect to the inhibition of 125I-IGF-I binding by unlabelled IGF-I and insulin. By contrast, the affinity of hybrids for insulin was approx. 10-fold lower than that of classical insulin receptors, as assessed by inhibition of 125I-insulin binding by unlabelled hormone. It is concluded that the properties of insulin receptors, but not IGF receptors, are markedly affected by assembly as hybrid compared with classical structures, and that hybrids are more likely to be responsive to IGF-I than insulin under physiological conditions.