| 1. |
- Åberg, N David, 1970, et al.
(författare)
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Insulin-like growth factor-I increases astrocyte intercellular gap junctional communication and connexin43 expression in vitro.
- 2003
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Ingår i: Journal of neuroscience research. - : Wiley. - 0360-4012. ; 74:1, s. 12-22
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Tidskriftsartikel (refereegranskat)abstract
- Connexin43 (cx43) forms gap junctions in astrocytes, and these gap junctions mediate intercellular communication by providing transport of low-molecular-weight metabolites and ions. We have recently shown that systemic growth hormone increases cx43 in the brain. One possibility was that local brain insulin-like growth factor-I (IGF-I) could mediate the effect by acting directly on astrocytes. In the present study, we examined the effects of direct application of recombinant human IGF-I (rhIGF-I) on astrocytes in primary culture concerning cx43 protein expression and gap junctional communication (GJC). After 24 hr of stimulation with rhIGF-I under serum-free conditions, the GJC and cx43 protein were analyzed. Administration of 30 ng/ml rhIGF-I increased the GJC and the abundance of cx43 protein. Cell proliferation of the astrocytes was not significantly increased by rhIGF-I at this concentration. However, a higher concentration of rhIGF-I (150 ng/ml) had no effect on GJC/cx43 but increased cell proliferation. Because of the important modulatory role of IGF binding proteins (IGFBPs) on IGF-I action, we analyzed IGFBPs in conditioned media. In cultures with a low abundance of IGFBPs (especially IGFBP-2), the GJC response to 30 ng/ml rhIGF-I was 81%, compared with the average of 25%. Finally, as a control, insulin was given in equimolar concentrations. However, GJC was not affected, which suggests that rhIGF-I acted via IGF-I receptors. In summary, the data show that rhIGF-I may increase GJC/cx43, whereas a higher concentration of rhIGF-I--at which stimulation of proliferation occurred--did not affect GJC/cx43. Furthermore, IGFBP-2 appeared to modulate the action of rhIGF-I on GJC in astrocytes by a paracrine mechanism.
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| 2. |
- Bang, Peter, et al.
(författare)
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Free dissociable IGF-I : Association with changes in IGFBP-3 proteolysis and insulin sensitivity after surgery
- 2016
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Ingår i: Clinical Nutrition. - : Churchill Livingstone. - 0261-5614 .- 1532-1983. ; 35:2, s. 408-413
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Tidskriftsartikel (refereegranskat)abstract
- Background: Patients receiving a carbohydrate drink (CHO) before major abdominal surgery display improved insulin sensitivity postoperatively and increased proteolysis of IGFBP-3 (IGFBP-3-PA) compared to patients undergoing similar surgery after overnight fasting. Aims: We hypothesized that serum IGFBP-3-PA increases bioavailability of circulating IGF-I and preserves insulin sensitivity in patients given CHO. Design: Matched control study. Methods: At Karolinska University Hospital, patients given CHO before major elective abdominal surgery (CHO,n = 8) were compared to patients undergoing similar surgical procedures after overnight fasting (FAST,n = 10). Results from two different techniques for determination of free-dissociable IGF-I (fdIGF-I) were compared with changes in IGFBP-3-PA and insulin sensitivity. Results: Postoperatively, CHO displayed 18% improvement in insulin sensitivity (hyperinsulinemic clamp) and increased IGFBP-3-PA vs. FAST. As determined by IRMA, fdIGF-I increased by 48 +/- 25% in CHO while fdIGF-I decreased by 13 +/- 18% in FAST (p < 0.01 vs. CHO, when corrected for duration of surgery). However, fdIGF-I determined by ultra-filtration decreased similarly in both groups (-22 +/- 8% vs. -25 +/- 8%, p = 0.8) and IGFBP-1 increased similarly in both groups. Patients with less insulin resistance after surgery demonstrated larger increases in fdIGF-I by IRMA (r = 0.58, p < 0.05). Fifty-three % of the variability of the changes in fdIGF-I by IRMA could be explained by changes in IGFBP-3-PA and total IGF-I levels (p < 0.05), while IGFBP-1 did not contribute significantly. Conclusion: During conditions when serum IGF-I bioavailability is regulated by IGFBP-3 proteolysis, measurements of fdIGF-I by IRMA is of physiological relevance as it correlates with the associated changes in insulin sensitivity.
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| 3. |
- Berg, Ulrika, et al.
(författare)
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Lack of sex differences in the IGF-IGFBP response to ultra endurance exercise.
- 2008
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Ingår i: Scandinavian Journal of Medicine and Science in Sports. - : Wiley. - 0905-7188 .- 1600-0838. ; 18:6, s. 706-714
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Tidskriftsartikel (refereegranskat)abstract
- The insulin-like growth factor (IGF)-IGF binding proteins (BP) and the pituitary-gonadal axes were investigated during ultra endurance exercise in 16 endurance-trained athletes (seven women). Median duration of the race was 6.3 days. Although food and drink were ad libitum, energy balance was negative. Blood samples were drawn before (PRE), at the end of (END) and 24 h after (POST24h) the race. Serum concentrations of total IGF-I (t-IGF-I) and free IGF-I (f-IGF-I) decreased by 33 (SD 38)% and 54 (19)%, respectively. The decrease in t-IGF-I appeared to be associated to the total energy deficit during the race. At END, the IGFBP-3 fragmentation and IGFBP-1 were increased but these changes did not predict changes in f-IGF-I. An increase in POST24h IGFBP-2 levels in women was the only sex difference. Testosterone was decreased by 67 (12)% in the men and estradiol became undetectable in the women without any detectable increase in LH and/or FSH. In conclusion ultra endurance exercise results in similar IGF-IGFBP responses in men and women reflecting a catabolic state. IGFBP-2 was the only exception, with increased levels in women after exercise. A concomitant decrease in gonadal hormones was not related to endocrine changes in the IGF-IGFBP axis but may be related to local changes in IGF-I expression.
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| 4. |
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| 5. |
- Carlsson-Skwirut, Christine, 1954-
(författare)
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Studies on mitochondrial adenosine triphosphatase : uncoupler-reversible inhibition of mitochondrial ATPase and related enzymes by metal chelates of bathophenenthroline
- 1982
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The mitochondrial ATPase constitutes the terminal enzyme of oxidative phosphorylation and is, together with similar enzymes present in chloroplasts and bacteria, responsible for the synthesis of ATP from ADP and Pi during electron transport. The enzyme consists of an extrinsic, catalytically active part, called Fl, that is structurally and functionally linked to an intrinsic, proton-translocating device, called Fo. It operates in this integrated form as a reversible proton pump, capable of utilizing a transmembrane proton gradient as the driving force for ATP synthesis.In our studies on the reaction mechanism of mitochondrial ATPase, we have found that both membrane-bound and soluble Fl are strongly and specifically inhibited by the Fe2+ trichelate, and other octahedral metal-trichelates, of bathophenanthroline (4,7-diphenyl-l, 10-phenanthroline, BPh) and that the inhibition is relieved by uncouplers of oxidative phosphorylation. It was shown that the inhibitor binds to the β-subunit of Fl (3 moles/mole Fl) and that the reversal of the inhibition by uncouplers involves a binding of the uncouplers to the inhibitory chelates, resulting in a catalytically active enzymeinhibitor- uncoupler complex.BPh3Fe2+ abolished the enhancement of aurovertin fluorescence in an uncoupler-reversible manner and converted the hyperbolic relationship found with soluble Fl between aurovertin concentration and enhancement of aurovertin fluorescence into sigmoidal. Similarly, the hyperbolic relationship between ATP concentration and the rate of ATP hydrolysis was rendered sigmoidal by BPh3Fe2+. These findings suggest that the chelate induces cooperativity between the β-subunits containing the active sites of the enzyme.BPh3Fe2+ protected soluble Fl against cold-inactivation and the concomitant dissociation of the enzyme. Likewise, BPh3Fe2+.prevented the light-dependent inactivation of Fl occurring in the presence of Rose Bengal. These effects of BPh3Fe2+ were also counteracted by uncouplers.In experiments performed with BPh3Ru2+, it was demonstrated that Fl enhances the fluorescence of this chelate about 5-fold, parallel to the inhibition of the enzyme, and that this fluorescence-enhancement is abolished by uncouplers along with the reversal of the inhibition.Finally, evidence was obtained that the BPh-metal chelate inhibition may occur generally with enzymes catalyzing the hydrolysis of pyrophosphate bonds. It was suggested that the inhibitory chelates may act by blocking a proton transfer between the active centers of these enzymes and the surrounding medium.
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| 6. |
- Ekstrom, Klas, et al.
(författare)
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Insulin-Like Growth Factor-I and Insulin-Like Growth Factor Binding Protein-3 Cotreatment versus Insulin-Like Growth Factor-I Alone in Two Brothers with Growth Hormone Insensitivity Syndrome: Effects on Insulin Sensitivity, Body Composition and Linear Growth
- 2011
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Ingår i: HORMONE RESEARCH IN PAEDIATRICS. - : Karger. - 1663-2818 .- 1663-2826. ; 76:5, s. 355-366
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Tidskriftsartikel (refereegranskat)abstract
- Background/Aims: Growth hormone insensitivity syndrome (GHIS) is caused by a defective growth hormone receptor (GHR) and is associated with insulin-like growth factor-I (IGF-I) deficiency, severely short stature and, from adolescence, fasting hyperglycemia and obesity. We studied the effects of treatment with IGF-I in either a 1:1 molar complex with IGFBP-3 (IGF-I/BP-3-Tx) or with IGF-I alone (IGF-I-Tx) on metabolism and linear growth. Methods: Two brothers, compound heterozygous for a GHR gene defect, were studied. After 8 months without treatment, we examined the short- and long-term effects of IGF-I/BP-3-Tx and, subsequently, IGF-I-Tx on 12-hour overnight levels of IGF-I, GH, insulin, IGFBP-1, insulin sensitivity by hyperinsulinemic euglycemic clamp, body composition by dual-energy X-ray absorptiometry and linear growth. Results: Mean overnight levels of insulin decreased and IGFBP-1, a measure of hepatic insulin sensitivity, increased on both regimens, but was more pronounced on IGF-I-Tx. Insulin sensitivity by clamp showed no consistent changes. Lean body mass increased and abdominal fat mass decreased in both subjects on IGF-I-Tx. However, the changes were inconsistent during IGF-I/BP-3-Tx. Height velocity was low without treatment, increased slightly on IGF-I/BP-3-Tx and doubled on IGF-I-Tx. Conclusion: Both modalities of IGF-I improved determinants of hepatic insulin sensitivity, body composition and linear growth rate; however, IGF-I alone seemed to be more efficient.
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| 7. |
- Ekstrom, Klas, et al.
(författare)
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Tissue IGF-I Measured by Microdialysis Reflects Body Glucose Utilization After rhIGF-I Injection in Type 1 Diabetes
- 2015
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Ingår i: Journal of Clinical Endocrinology and Metabolism. - : ENDOCRINE SOC. - 0021-972X .- 1945-7197. ; 100:11, s. 4299-4306
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Tidskriftsartikel (refereegranskat)abstract
- Context: Type 1 diabetes is associated with portal insulin deficiency and disturbances in the GH-IGF axis including low circulating IGF-I and GH hypersecretion. Whether peripheral hyperinsulinemia and GH hypersecretion, which are relevant to the development of vascular complications, result in elevated tissue IGF-I remains unknown. Objective: The purpose of this study was to determine the relationship between whole-body glucose uptake and tissue IGF-I measured by microdialysis. Design: This was a single-blind placebo-controlled crossover study. Setting: The setting was a tertiary pediatric endocrine referral center. Participants: The participants were seven young male adults with type 1 diabetes. Intervention: After an overnight fast, a 6-h lasting euglycemic clamp was performed (constant insulin infusion at 0.5mU/kg x minute and variable glucose infusion rate [GIR]) and a subcutaneous injection of recombinant human (rh) IGF-I (120 mu g/kg) or saline was given after 2 hours. In parallel, tissue IGF-I levels were determined by microdialysis (md-IGF-I). Main Outcome Measures: md-IGF-I levels in muscle and subcutaneous fat, and GIR were determined. Results: md-IGF-I levels were detectable but unchanged after saline. After rhIGF-I, muscle and subcutaneous fat md-IGF-I increased during the second and third hour and then reached a plateau up to 10-fold higher than baseline (P less than .001). GIR was unchanged after saline, whereas it increased 2.5-fold concomitantly with the increase in md-IGF-I (P less than .0001). In contrast, serum IGF-I was increased already at 30 minutes after rhIGF-I and reached a plateau 2-fold above baseline (P less than .0001). Conclusion: We demonstrate that md-IGF-I measurements are valid and physiologically relevant by reflecting rhIGF-I-induced glucose uptake. Future studies should be conducted to elucidate the role of local tissue IGF-I in diabetic vascular complications.
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| 8. |
- Åberg, Maria A I, 1972, et al.
(författare)
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IGF-I has a direct proliferative effect in adult hippocampal progenitor cells.
- 2003
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Ingår i: Molecular and cellular neurosciences. - 1044-7431. ; 24:1, s. 23-40
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Tidskriftsartikel (refereegranskat)abstract
- The aim of the present study was to investigate the potential direct effects of insulin-like growth factor-I (IGF-I) on adult rat hippocampal stem/progenitor cells (AHPs). IGF-I-treated cultures showed a dose-dependent increase in thymidine incorporation, total number of cells, and number of cells entering the mitosis phase. Pretreatment with fibroblast growth factor-2 (FGF-2) increased the IGF-I receptor (IGF-IR) expression, and both FGF-2 and IGF-I were required for maximal proliferation. Time-lapse recordings showed that IGF-I at 100 ng/ml decreased differentiation and increased proliferation of single AHPs. Specific inhibition of mitogen-activated protein kinase kinase (MAPKK), phosphatidylinositol 3-kinase (PI3-K), or the downstream effector of the PI3-K pathway, serine/threonine p70 S6 kinase (p70(S6K)), showed that both the MAPK and the PI3-K pathways participate in IGF-I-induced proliferation but that the MAPK activation is obligatory. These results were confirmed with dominant-negative constructs for these pathways. Stimulation of differentiation was found at a low dose (1 ng/ml) of IGF-I, clonal analysis indicating an instructive component of IGF-I signaling.
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