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  • 1.
    Bäck, Karolina
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
    Islam, Rakibul
    Linköping University, Department of Clinical and Experimental Medicine. Linköping University, Faculty of Health Sciences.
    Johansson, Git
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
    Chisalita, Ioana Simona
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Local Health Care Services in Central Östergötland, Department of Acute Health Care.
    Arnqvist, Hans
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Heart and Medicine Centre, Department of Endocrinology and Gastroenterology UHL.
    Insulin and IGF1 receptors in human cardiac microvascular endothelial cells: metabolic, mitogenic and anti-inflammatory effects2012In: Journal of Endocrinology, ISSN 0022-0795, E-ISSN 1479-6805, Vol. 215, no 1, p. 89-96Article in journal (Refereed)
    Abstract [en]

    Diabetes is associated with microcirculatory dysfunction and heart failure and changes in insulin and IGF1 levels. Whether human cardiac microvascular endothelial cells (HMVEC-Cs) are sensitive to insulin and/or IGF1 is not known. We studied the role of insulin receptors (IRs) and IGF1 receptors (IGF1Rs) in metabolic, mitogenic and anti-inflammatory responses to insulin and IGF1 in HMVEC-Cs and human umbilical vein endothelial cells (HUVECs). IR and IGF1R gene expression was studied using real-time RT-PCR. Receptor protein expression and phosphorylation were determined by western blot and ELISA. Metabolic and mitogenic effects were measured as glucose accumulation and thymidine incorporation. An E-selectin ELISA was used to investigate inflammatory responses. According to gene expression and protein in HMVEC-Cs and HUVECs, IGF1R is more abundant than IR. Immunoprecipitation with anti-IGF1R antibody and immunoblotting with anti-IR antibody and vice versa, showed insulin/IGF1 hybrid receptors in HMVEC-Cs. IGF1 at a concentration of 10(-8) mol/l significantly stimulated phosphorylation of both IGF1R and IR in HMVEC-Cs. In HUVECs IGF1 10(-8) mol/l phosphorylated IGF1R. IGF1 stimulated DNA synthesis at 10(-8) mol/l and glucose accumulation at 10(-7) mol/l in HMVEC-Cs. TNF-alpha dramatically increased E-selectin expression, but no inflammatory or anti-inflammatory effects of insulin, IGF1 or high glucose were seen. We conclude that HMVEC-Cs express more IGF1Rs than IRs, and mainly react to IGF1 due to the predominance of IGF1Rs and insulin/IGF1 hybrid receptors. TNF-alpha has a pronounced pro-inflammatory effect in HMVEC-Cs, which is not counteracted by insulin or IGF1.

  • 2.
    Bäck, Karolina
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
    Islam, Rakibul
    Linköping University, Department of Clinical and Experimental Medicine. Linköping University, Faculty of Health Sciences.
    Johansson, Git
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
    Chisalita, Simona
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Local Health Care Services in Central Östergötland, Department of Acute Health Care.
    Arnqvist, Hans
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Heart and Medicine Centre, Department of Endocrinology and Gastroenterology UHL.
    Role of insulin and IGF-I receptors in human cardiac microvascular endothelial cells; metabolic, mitogenic and anti-inflammatory effectsManuscript (preprint) (Other academic)
    Abstract [en]

    Diabetes is associated with coronary microcirculatory dysfunction and heart failure as well as changes in insulin and IGF-I levels. Our aim was to study the role of insulin receptors and IGF-I receptors in metabolic, mitogenic and anti-inflammatory responses to insulin and IGF-I in human cardiac microvascular endothelial cells (HMVEC-C) and, for comparison, also human umbilical vein endothelial cells (HUVEC). Insulin receptor (IR) and IGF-I receptor (IGF-IR) gene expression was studied with real-time RT-PCR. Receptor protein expression and phosphorylation was determined with Western blot and ELISA. The metabolic and mitogenic effects were measured as glucose accumulation and thymidine incorporation. An E-selectin ELISA was used to investigate the anti-inflammatory responses. IGF-IR was more abundant than IR both regarding gene expression and protein in HMVEC-C and HUVEC. Immunoprecipitation with anti-IGF-IR antibody and immunoblotting with anti-IR antibody and vice versa, showed insulin/IGF-I hybrid receptors in these cells. IGF-I 10-8 M significantly stimulated phosphorylation of both IGF-IR and IR in HMVEC-C. In HUVEC IGF-I 10-8 M phosphorylated IGF-IR. IGF-I also stimulated DNA synthesis at 10-8 M and glucose accumulation at 10-7 M. TNF-α significantly increased E-selectin expression whereas no effects were found by insulin, IGF-I or high glucose.

    We conclude that HMVEC-C express more IGF-I receptors than insulin receptors and at physiological concentrations of insulin and IGF-I mainly reacts to IGF-I probably due to the predominance of IGF-I receptors and insulin/IGF-I hybrid receptors. TNF-α has a pronounced pro-inflammatory effect in HMVEC-C which is not counteracted by insulin or IGF-I.

  • 3.
    Chisalita, Ioana Simona
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Local Health Care Services in Central Östergötland, Department of Acute Health Care.
    Dahlström, Ulf
    Linköping University, Department of Medical and Health Sciences, Cardiology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Heart and Medicine Centre, Department of Cardiology UHL.
    Arnqvist, Hans
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Heart and Medicine Centre, Department of Endocrinology and Gastroenterology UHL.
    Alehagen, Urban
    Linköping University, Department of Medical and Health Sciences, Cardiology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Heart and Medicine Centre, Department of Cardiology UHL.
    Increased IGF1 levels in relation to heart failure and cardiovascular mortality in an elderly population: impact of ACE inhibitors2011In: European Journal of Endocrinology, ISSN 0804-4643, E-ISSN 1479-683X, Vol. 165, no 6, p. 891-898Article in journal (Refereed)
    Abstract [en]

    Objective: There are conflicting results regarding the association of circulating IGF1 with cardiovascular (CV) morbidity and mortality. We assessed the relationship between IGF1 levels and heart failure (HF), ischemic heart disease (IHD), and CV mortality in an elderly population taking into account the possible impact of angiotensin converting enzyme (ACE) inhibitors. Design and methods: A total of 851 persons aged 66-81 years, in a rural Swedish municipality, were subjected to medical history, clinical examination, electrocardiography, echocardiography, and fasting plasma samples. They were then followed for 8 years. Results and conclusion: Patients on ACE inhibitors had higher IGF1 levels compared with those without ACE inhibitors. In patients on ACE inhibitors, higher IGF1 values were found in patients with an ejection fraction (EF) less than40% compared with EF greater than= 40%, in patients with higher proBNP levels in quartile 4 vs 1, and in patients with IHD when compared to those without ACE inhibitors (P less than 0.001). In patients without ACE inhibitors, no relationship was found between IGF1 levels and HF or IHD. In multivariate regression, only ACE inhibitors, ECG changes characteristic for IHD, and gender had a significant impact on IGF1. Patients with higher IGF1 levels in quintiles 4 and 5 compared to quintiles 1 and 2 had a 50% higher risk for CV death (P=0.03). This was significant after adjustment for well-known CV risk factors and ACE inhibitors (P=0.03). Conclusions: Our results show that treatment with ACE inhibitors in an elderly population is associated with increased IGF1 levels, especially in patients with impaired cardiac function or IHD. High IGF1 levels tend to be associated with an increased risk for CV mortality.

  • 4.
    Chisalita, Ioana Simona
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Local Health Care Services in Central Östergötland, Department of Acute Health Care in Linköping.
    Dahlström, Ulf
    Linköping University, Department of Medical and Health Sciences, Division of Cardiovascular Medicine. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Heart and Medicine Center, Department of Cardiology in Linköping.
    Arnqvist, Hans
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Heart and Medicine Center, Department of Endocrinology.
    Alehagen, Urban
    Linköping University, Department of Medical and Health Sciences, Division of Cardiovascular Medicine. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Heart and Medicine Center, Department of Cardiology in Linköping.
    Proinsulin and IGFBP-1 predicts mortality in an elderly population2014In: International Journal of Cardiology, ISSN 0167-5273, E-ISSN 1874-1754, Vol. 174, no 2, p. 260-267Article in journal (Refereed)
    Abstract [en]

    BACKGROUND:

    High IGFBP-1 in elderly subjects is related to all-cause and cardiovascular (CV) mortality. We studied the relation of IGFBP-1 to cardiometabolic risk factors and cardiovascular and all-cause mortality, and also the impact of proinsulin and insulin on this association in an unselected elderly primary health care population.

    HYPOTHESIS:

    Our hypothesis was that proinsulin and insulin may have an impact on the association of high IGFBP-1 levels with all-cause and CV-mortality in elderly.

    DESIGN, SETTING AND PARTICIPANTS:

    A cross-sectional and prospective study was carried out in a rural Swedish population. 851 persons aged 66-81 years were evaluated by medical history, clinical examination, electrocardiography, echocardiography, and fasting plasma samples, and were followed prospectively for up to 12 years.

    RESULTS:

    At baseline, in a multivariate analysis, IGFBP-1 was associated with gender, N-terminal proBNP (NT pro-BNP), blood glucose, body mass index (BMI), insulin and proinsulin, estimated glomerular filtration rate (eGFR) and haemoglobin (Hb). During the follow-up period there were 230 deaths (27%), of which 134 (16%) were due to CV mortality. When divided into tertiles there was a significant difference for CV mortality and all-cause mortality between tertiles of IGFBP-1 and proinsulin. For insulin there was a significant difference only for all-cause mortality. After adjustment for well-known risks factors, proinsulin and IGFBP-1 had significant impact on all-cause mortality but only proinsulin on CV mortality.

    CONCLUSION:

    Only proinsulin is an independent predictor for both all-cause mortality and CV mortality when comparing IGFBP-1, insulin, and proinsulin as prognostic biomarkers for CV and all-cause mortality in an elderly population.

  • 5.
    Chisalita, Ioana Simona
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Local Health Care Services in Central Östergötland, Department of Acute Internal Medicine.
    Johansson, Git
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
    Liefvendahl, Ellinor
    Linköping University, Department of Clinical and Experimental Medicine. Linköping University, Faculty of Health Sciences.
    Bäck, Karolina
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
    Arnqvist, Hans
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Medicine, Department of Endocrinology and Gastroenterology UHL.
    Human aortic smooth muscle cells are insulin resistant at the receptor level but sensitive to IGF1 and IGF22009In: Journal of Molecular Endocrinology, ISSN 0952-5041, E-ISSN 1479-6813, Vol. 43, no 5-6, p. 231-239Article in journal (Refereed)
    Abstract [en]

    Whether insulin, in physiological concentrations, has direct effects on vascular smooth muscle cells (VSMC) remains controversial. Our aim was to characterize the mechanism for insulin resistance in VSMCs. For comparison, effects of insulin-like growth factor (IGF)-I and IGF-II were also studied. Cultured human aortic smooth muscle cells (HASMC) were used. Receptor mRNA was analysed by quantitative RT-PCR and receptor protein by ELISA and Western Blot. The biological effects were studied by thymidine incorporation and glucose accumulation.

    In HASMC both mRNA and protein expression of IGF-I receptors (IGF-IR) were 5 fold higher compared to insulin receptor (IR). IR isoform A mRNA was 13 times more expressed than IR isoform B. Immunoprecipitation and Western blot showed co precipitation of IR and IGF-IR indicating the presence of hybrid IR/IGF-IR.

    Phosphorylation of the IGF-IR β-subunit was obtained by IGF-I 10-9-10-8mol l-1 and IGF-II 10-8mol l-1. IR β-subunit was phosphorylated by IGF-I 10-8mol l-1 but not by insulin. IGF-I stimulated IRS-I at 10-8mol l-1, Akt and Erk 1/2 at 10-9-10-8mol l-1, respectively. IGF-II stimulated Akt at 10-8mol l-1 whereas insulin had no effect. IGF-I and IGF-II at a concentration of 10-8-10-7mol l-1 significantly stimulated 3H-thymidine incorporation, whereas insulin did not. 14C-Glucose accumulation was stimulated by IGF-I or IGF-II 10-8-10-7mol l-1, and also by insulin 10-7mol l-1.

    Our results suggest that IGF-IR and hybrid IR/IGF-IR are activated by physiological concentrations of IGF-I and IGF-II in HASMC and this causes downstream signaling and biological effects, while insulin has no effect on its receptor or downstream signaling probably due to a preponderance of IGF-IR and incorporation of IR into hybrid IR/IGF-IR.

  • 6.
    Chisalita, Simona I.
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Local Health Care Services in Central Östergötland, Department of Acute Internal Medicine.
    Expression and function of IGF-I and insulin receptors in human micro- and macrovascular cells2008Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Insulin-like growth factor and insulin are phylogenetically closely related polypeptides and have large structural and biological similarities. Low circulating insulin-like growth factor-I (IGF-I), diabetes as well as insulin resistance have been implicated in the pathogenesis of cardiovascular disease, but the mechanisms involved are still not clear. Furthermore, little is known about direct effects of insulin-like growth factor-I (IGF-I) and insulin on human micro- and macrovascular cells.

    In these studies we investigated the expression and function of insulin-like growth factor-I receptors (IGF-IR) and insulin receptors (IR) in human micro- and macrovascular endothelial cells and in human coronary artery smooth muscle cells.

    Our results showed expression of both IGF-IR and IR in human dermal microvascular (HMVEC), aortic (HAEC) umbilical vein (HUVEC) and coronary artery (HCAEC) endothelial cells as well as in human coronary artery smooth muscle cells (HASMC). The gene expression of IGF-IR was several times more abundant than that of IR. Ligand binding studies confirmed that the IGF-IR was severalfold more abundant than the IR. It also demonstrated that insulin and glargine interacted with the IGF-IR with thousand- and hundredfold, respectively, less potency than IGF-I itself. The presence of IGF-IR and IR proteins and activation of their β-subunits was revealed by immunoprecipitation and Western blot analysis in human macrovascular endothelial cells and in coronary artery smooth muscle cells. At physiological concentrations (≤10-9 M) IGF-I and insulin activated their cognate receptors. The presence of hybrid IR/IGF-IR was shown through detection of the β-subunit for IGF-IR and IR on the same membrane by Western blot after immunoprecipitation with specific antibodies against either IGF-IR or IR, implying coprecipitation of the IGF-IR β-subunit and the IR β-subunit. The inability of physiological concentrations of insulin to phosphorylate IR β-subunit immunoprecipitated with IGF-IR antibodies and that IGF-I at physiological concentration activates the IR β-subunit is another evidence for the presence of the hybrid IR/IGF-IR. At physiological concentrations (≤10-9 M) IGF-I stimulated DNA synthesis and glucose incorporation into human coronary artery smooth muscle cells (HCASMC) and DNA synthesis in microvascular endothelial cells (HMVEC), but not in human macrovascular endothelial cells (HCAEC or HUVEC). No effect of insulin was found. Although physiological concentrations of insulin (≤10-9 M) were able to activate IR, insulin had no biological effects on the vascular cells studied. A possible explanation is that the insulin receptor signalling is too attenuated due to the presence of hybrid IR/IGF-IR and low number of IR expressed in the cells studied. Regarding the safety in the use of glargine, we show that glargine has 10-fold higher affinity for IGF-IR than human insulin. However, the glargine concentrations obtained in vivo during diabetes treatment is too low to affect the IGF-IR.

    In conclusions our studies provide experimental evidence that human micro- and macrovascular endothelial and vascular smooth muscle cells express both IGF-IR and IR. Our in vitro data suggest that the cells studied are sensitive to IGF-I, but insensitive to insulin and this is due to the preponderance of IGF-IR and presence of hybrid IR/IGF-IR.

    List of papers
    1. Insulin-like growth factor I receptors are more abundant than insulin receptors in human micro- and macrovascular endothelial cells
    Open this publication in new window or tab >>Insulin-like growth factor I receptors are more abundant than insulin receptors in human micro- and macrovascular endothelial cells
    2004 (English)In: American Journal of Physiology. Endocrinology and Metabolism, ISSN 0193-1849, E-ISSN 1522-1555, Vol. 286, p. E896-E901Article in journal (Refereed) Published
    Abstract [en]

    Micro- and macroangiopathy are major causes of morbidity and mortality in patients with diabetes. Our aim was to characterize IGF-I receptor (IGF-IR) and insulin receptor (IR) in human micro- and macrovascular endothelial cells. Cultured human dermal microvascular endothelial cells (HMVEC) and human aortic endothelial cells (HAEC) were used. Gene expression was measured by quantitative real-time RT-PCR and receptor protein by ligand-binding assay. Phosphorylation of IGF-IR ß-subunit was analyzed by immunoprecipitation and Western blot. Glucose metabolism and DNA synthesis was assessed using [3H]glucose and [3H]thymidine incorporation, respectively. We detected gene expression of IGF-IR and IR in HAEC and HMVEC. IGF-IR gene expression was severalfold higher than that of IR. The specific binding of 125I-IGF-I was higher than that of 125I-insulin in HAEC and HMVEC. Insulin and the new, long-acting insulin analog glargine interacted with the IGF-IR with thousand- and hundred-fold less potency than IGF-I itself. Phosphorylation of the IGF-IR ß-subunit was shown in HAEC for IGF-I (10-8 M) and insulin (10-6 M) and in HMVEC for IGF-I and glargine (10-8 M, 10-6 M). IGF-I 10-7 M stimulated incorporation of [3H]thymidine into DNA, and 10-9–10-7 M also the incorporation of [3H]glucose in HMVEC, whereas glargine and insulin had no significant effects at 10-9–10-7 M. Human micro- and macrovascular endothelial cells express more IGF-IR than IR. IGF-I and high concentrations of glargine and insulin  ctivates the IGF-IR. Glargine has a higher affinity than insulin for the IGF-IR but probably has no effect on DNA synthesis at concentrations reached in vivo.

    Keywords
    Human endothelial cells, receptor, insulin, glargine
    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:liu:diva-12552 (URN)10.1152/ajpendo.00327.2003 (DOI)
    Available from: 2008-09-15 Created: 2008-09-15 Last updated: 2017-12-14
    2. IGF-I/insulin hybrid receptors in human endothelial cells
    Open this publication in new window or tab >>IGF-I/insulin hybrid receptors in human endothelial cells
    Show others...
    2005 (English)In: Molecular and Cellular Endocrinology, ISSN 0303-7207, E-ISSN 1872-8057, Vol. 229, no 1-2, p. 31-37Article in journal (Refereed) Published
    Abstract [en]

    Vascular complications are common in diabetes. IGF-I receptors (IGF-IR) and insulin receptors (IR) in endothelial cells might respond to altered levels of IGF-I and insulin, resulting in altered endothelial function in diabetes. We therefore studied IGF-IR and IR gene expression, ligand binding, receptor protein, and phosphorylation in human umbilical vein endothelial cells (HUVEC). IGF-IR mRNA was more abundant than IRmRNAin freshly isolatedHUVEC(IGF-IR/IR ratio 7.1±1.5) and in culturedHUVEC(ratio 3.5±0.51). Accordingly, specific binding of 125I-IGF-I (0.64±0.25%) was higher than that of 125I-insulin (0.25±0.09%). Protein was detected for both  eceptors and IGF-I/insulin hybrid receptors. IGF-IR phosphorylation was stimulated by 10−10 to 10−8M IGF-I. IR were activated by 10−9 to 10−8M insulin and IGF-I. We conclude that HUVEC express more IGF-IR than IR, and also express hybrid receptors. Both IGF-I and insulin phosphorylate their own receptors but only IGF-I seems to phosphorylate hybrid receptors.

    Keywords
    IGF-I receptor; Insulin receptor; Insulin/IGF-I hybrid receptor; Endothelial cells; Human
    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:liu:diva-12553 (URN)10.1016/j.mce.2004.10.003 (DOI)000226596400005 ()
    Available from: 2008-09-15 Created: 2008-09-15 Last updated: 2017-12-14
    3. Characterisation of receptors for IGF-I and insulin: evidence for hybrid insulin/IGF-I receptor in human coronary artery endothelial cells
    Open this publication in new window or tab >>Characterisation of receptors for IGF-I and insulin: evidence for hybrid insulin/IGF-I receptor in human coronary artery endothelial cells
    2006 (English)In: Growth Hormone & IGF Research, ISSN 1096-6374, E-ISSN 1532-2238, Vol. 16, no 4, p. 258-266Article in journal (Refereed) Published
    Abstract [en]

    Objective: Coronary artery disease is a prevalent cause of morbidity and mortality in diabetes. Little is known about insulin-like growth factor-I receptors (IGF-IR) and insulin receptors (IR) in human coronary endothelium. Our aim was to characterize IGF-IR and IR in human coronary artery endothelial cells (HCAEC).

    Design: Cultured human coronary artery endothelial cells were used. Gene expression was measured by quantitative real-time RTPCR analysis and receptor affinity by ligand binding. Receptor protein, phosphorylation of IGF-IR and IR b-subunit as well as the presence of hybrid insulin receptor/Insulin-like growth factor-I receptor (Hybrid IR/IGF-IR) was analyzed by immunoprecipitation and Western blot. Postreceptor effects of insulin and IGF-I were assed by 3H-thymidine incorporation.

    Results: The gene expression of IGF-IR was several folds higher than that of IR. and insulin receptor isoform A (IR-A) was 20-fold more expressed than insulin receptor isoform B (IR-B) in HCAEC. The specific binding of 125I-IGF-I was higher than that of 125Iinsulin. Insulin and the new long acting insulin analog, glargine, interacted with the IGF-IR with over thousand and 100-fold less potency than IGF-I itself, whereas IGF-II had 6 times lower potency than IGF-I. Phosphorylation of the IGF-IR b-subunit was obtained by concentrations of 10-10–10-8 M IGF-I, 10-6 M of insulin, inconsistently by 10-8 M insulin and not at all by 10-10–10-9 M insulin. The IR b-subunit was phosphorylated by insulin and IGF-I at concentrations of 10-9–10-8 M. When immunoprecipitating with specific monoclonal anti-IR or anti-IGF-IR a-subunit antibodies we found bands situated in slightly different positions suggesting the presence of Hybrid IR/IGF-IR. IGF-I, IGF-II and insulin (10-9–10-7 M) had no significant effect on 3H-thymidine incorporation into DNA.

    Conclusions: Human coronary endothelial cells express more IGF-IR than IR, mainly IR-A, and also Hybrid IR/IGF-IR. Both IGF-I and insulin phosphorylate their receptors, but only IGF-I seems to phosphorylate Hybrid IR/IGF-IR. Our study provides experimental evidence for a possible role of IGF-IR, IR and Hybrid IR/IGF-IR in human coronary artery endothelial cells.

    Keywords
    Human endothelial cells; Insulin-like growth factor-I; Insulin
    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:liu:diva-12555 (URN)10.1016/j.ghir.2006.06.003 (DOI)000240947800006 ()
    Available from: 2008-09-15 Created: 2008-09-15 Last updated: 2017-12-14
    4. Expression and function of receptors for insulin-like growth factor-I and insulin in human coronary artery smooth muscle cells
    Open this publication in new window or tab >>Expression and function of receptors for insulin-like growth factor-I and insulin in human coronary artery smooth muscle cells
    2005 (English)In: Diabetologia, ISSN 0012-186X, E-ISSN 1432-0428, Vol. 48, no 10, p. 2155-2161Article in journal (Refereed) Published
    Abstract [en]

    Aims/hypothesis: Hyperinsulinaemia and insulin resistance, as well as low IGF-I, have been implicated in the pathogenesis of cardiovascular disease. Little is known about direct effects of IGF-I and insulin on human coronary artery smooth muscle cells (HCASMCs). Our aim was to characterise the expression and function of IGF-I receptor (IGF-IR) and insulin receptor (IR) in HCASMCs. Materials and methods: Cultured HCASMCs were used. mRNA expression was measured by quantitative real-time RT-PCR analysis. Receptor proteins, phosphorylation of β-subunits and the presence of hybrid IR/IGF-IR were analysed by immunoprecipitation and western blotting. DNA synthesis and glucose metabolism were assessed using [3H]thymidine incorporation and D-[U-14C]glucose accumulation respectively. Results: The mRNA expression of IGF-IR was approximately eight-fold higher than that of IR in HCASMCs. The presence of IGF-IR and IR could be demonstrated by immunoprecipitation and western blot analysis. Phosphorylation of the IGF-IR β-subunit was obtained by IGF-I at 10−10–10−8 mol/l and insulin at 10−8 mol/l. Insulin and IGF-I at 10−10–10−9 mol/l phosphorylated the IR β-subunit. When immunoprecipitated with monoclonal anti-IR α-subunit or IGF-IR α-subunit antibodies, we found bands in slightly different positions, suggesting the presence of hybrid IR/IGF-IR. IGF-I at 10−9–10−8 mol/l significantly stimulated [3H]thymidine incorporation and at a concentration of 10−9–10−7 mol/l also D-[U-14C]glucose accumulation in HCASMCs. Insulin at 10−9–10−7 mol/l had no effect on DNA synthesis, but increased glucose accumulation at 10−7 mol/l. Conclusions/interpretation: Our study provides experimental evidence that IGF-IR and possibly hybrid IR/IGF-IR play a role in HCASMCs.

    Keywords
    Human coronary artery smooth muscle cells, Hybrid insulin receptor/IGF-I receptor, IGF-I receptor, Insulin receptor
    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:liu:diva-12556 (URN)10.1007/s00125-005-1890-4 (DOI)
    Available from: 2008-09-15 Created: 2008-09-15 Last updated: 2017-12-14
  • 7.
    Chisalita, Simona I.
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Cellbiology. Linköping University, Faculty of Health Sciences.
    Arnqvist, Hans J.
    Linköping University, Department of Clinical and Experimental Medicine, Cellbiology. Linköping University, Faculty of Health Sciences.
    Expression and function of receptors for insulin-like growth factor-I and insulin in human coronary artery smooth muscle cells2005In: Diabetologia, ISSN 0012-186X, E-ISSN 1432-0428, Vol. 48, no 10, p. 2155-2161Article in journal (Refereed)
    Abstract [en]

    Aims/hypothesis: Hyperinsulinaemia and insulin resistance, as well as low IGF-I, have been implicated in the pathogenesis of cardiovascular disease. Little is known about direct effects of IGF-I and insulin on human coronary artery smooth muscle cells (HCASMCs). Our aim was to characterise the expression and function of IGF-I receptor (IGF-IR) and insulin receptor (IR) in HCASMCs. Materials and methods: Cultured HCASMCs were used. mRNA expression was measured by quantitative real-time RT-PCR analysis. Receptor proteins, phosphorylation of β-subunits and the presence of hybrid IR/IGF-IR were analysed by immunoprecipitation and western blotting. DNA synthesis and glucose metabolism were assessed using [3H]thymidine incorporation and D-[U-14C]glucose accumulation respectively. Results: The mRNA expression of IGF-IR was approximately eight-fold higher than that of IR in HCASMCs. The presence of IGF-IR and IR could be demonstrated by immunoprecipitation and western blot analysis. Phosphorylation of the IGF-IR β-subunit was obtained by IGF-I at 10−10–10−8 mol/l and insulin at 10−8 mol/l. Insulin and IGF-I at 10−10–10−9 mol/l phosphorylated the IR β-subunit. When immunoprecipitated with monoclonal anti-IR α-subunit or IGF-IR α-subunit antibodies, we found bands in slightly different positions, suggesting the presence of hybrid IR/IGF-IR. IGF-I at 10−9–10−8 mol/l significantly stimulated [3H]thymidine incorporation and at a concentration of 10−9–10−7 mol/l also D-[U-14C]glucose accumulation in HCASMCs. Insulin at 10−9–10−7 mol/l had no effect on DNA synthesis, but increased glucose accumulation at 10−7 mol/l. Conclusions/interpretation: Our study provides experimental evidence that IGF-IR and possibly hybrid IR/IGF-IR play a role in HCASMCs.

  • 8.
    Chisalita, Simona I.
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
    Dekker Nitert, Marloes
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
    Arnqvist, Hans J.
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
    Characterisation of receptors for IGF-I and insulin: evidence for hybrid insulin/IGF-I receptor in human coronary artery endothelial cells2006In: Growth Hormone & IGF Research, ISSN 1096-6374, E-ISSN 1532-2238, Vol. 16, no 4, p. 258-266Article in journal (Refereed)
    Abstract [en]

    Objective: Coronary artery disease is a prevalent cause of morbidity and mortality in diabetes. Little is known about insulin-like growth factor-I receptors (IGF-IR) and insulin receptors (IR) in human coronary endothelium. Our aim was to characterize IGF-IR and IR in human coronary artery endothelial cells (HCAEC).

    Design: Cultured human coronary artery endothelial cells were used. Gene expression was measured by quantitative real-time RTPCR analysis and receptor affinity by ligand binding. Receptor protein, phosphorylation of IGF-IR and IR b-subunit as well as the presence of hybrid insulin receptor/Insulin-like growth factor-I receptor (Hybrid IR/IGF-IR) was analyzed by immunoprecipitation and Western blot. Postreceptor effects of insulin and IGF-I were assed by 3H-thymidine incorporation.

    Results: The gene expression of IGF-IR was several folds higher than that of IR. and insulin receptor isoform A (IR-A) was 20-fold more expressed than insulin receptor isoform B (IR-B) in HCAEC. The specific binding of 125I-IGF-I was higher than that of 125Iinsulin. Insulin and the new long acting insulin analog, glargine, interacted with the IGF-IR with over thousand and 100-fold less potency than IGF-I itself, whereas IGF-II had 6 times lower potency than IGF-I. Phosphorylation of the IGF-IR b-subunit was obtained by concentrations of 10-10–10-8 M IGF-I, 10-6 M of insulin, inconsistently by 10-8 M insulin and not at all by 10-10–10-9 M insulin. The IR b-subunit was phosphorylated by insulin and IGF-I at concentrations of 10-9–10-8 M. When immunoprecipitating with specific monoclonal anti-IR or anti-IGF-IR a-subunit antibodies we found bands situated in slightly different positions suggesting the presence of Hybrid IR/IGF-IR. IGF-I, IGF-II and insulin (10-9–10-7 M) had no significant effect on 3H-thymidine incorporation into DNA.

    Conclusions: Human coronary endothelial cells express more IGF-IR than IR, mainly IR-A, and also Hybrid IR/IGF-IR. Both IGF-I and insulin phosphorylate their receptors, but only IGF-I seems to phosphorylate Hybrid IR/IGF-IR. Our study provides experimental evidence for a possible role of IGF-IR, IR and Hybrid IR/IGF-IR in human coronary artery endothelial cells.

  • 9.
    Chisalita, Simona Ioana
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Local Health Care Services in Central Östergötland, Department of Acute Internal Medicine.
    Arnqvist, Hans J.
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Medicine, Department of Endocrinology and Gastroenterology UHL.
    Insulin-like growth factor I receptors are more abundant than insulin receptors in human micro- and macrovascular endothelial cells2004In: American Journal of Physiology. Endocrinology and Metabolism, ISSN 0193-1849, E-ISSN 1522-1555, Vol. 286, p. E896-E901Article in journal (Refereed)
    Abstract [en]

    Micro- and macroangiopathy are major causes of morbidity and mortality in patients with diabetes. Our aim was to characterize IGF-I receptor (IGF-IR) and insulin receptor (IR) in human micro- and macrovascular endothelial cells. Cultured human dermal microvascular endothelial cells (HMVEC) and human aortic endothelial cells (HAEC) were used. Gene expression was measured by quantitative real-time RT-PCR and receptor protein by ligand-binding assay. Phosphorylation of IGF-IR ß-subunit was analyzed by immunoprecipitation and Western blot. Glucose metabolism and DNA synthesis was assessed using [3H]glucose and [3H]thymidine incorporation, respectively. We detected gene expression of IGF-IR and IR in HAEC and HMVEC. IGF-IR gene expression was severalfold higher than that of IR. The specific binding of 125I-IGF-I was higher than that of 125I-insulin in HAEC and HMVEC. Insulin and the new, long-acting insulin analog glargine interacted with the IGF-IR with thousand- and hundred-fold less potency than IGF-I itself. Phosphorylation of the IGF-IR ß-subunit was shown in HAEC for IGF-I (10-8 M) and insulin (10-6 M) and in HMVEC for IGF-I and glargine (10-8 M, 10-6 M). IGF-I 10-7 M stimulated incorporation of [3H]thymidine into DNA, and 10-9–10-7 M also the incorporation of [3H]glucose in HMVEC, whereas glargine and insulin had no significant effects at 10-9–10-7 M. Human micro- and macrovascular endothelial cells express more IGF-IR than IR. IGF-I and high concentrations of glargine and insulin  ctivates the IGF-IR. Glargine has a higher affinity than insulin for the IGF-IR but probably has no effect on DNA synthesis at concentrations reached in vivo.

  • 10.
    Chisalita, Simona Ioana
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Local Health Care Services in Central Östergötland, Department of Acute Internal Medicine.
    Lindström, Torbjörn
    Linköping University, Department of Medical and Health Sciences, Internal Medicine. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Medicine, Department of Endocrinology and Gastroenterology UHL.
    Eson Jennersjö, Pär
    Borensberg Health Centre, Linköping.
    Paulsson, Johan
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
    Westermark, Gunilla
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
    Olsson, Anders
    Linköping University, Department of Medical and Health Sciences, Internal Medicine. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Medicine, Department of Endocrinology and Gastroenterology UHL.
    Arnqvist, Hans
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Medicine, Department of Endocrinology and Gastroenterology UHL.
    Differential lipid profile and hormonal response in type 2 diabetes by exogenous insulin aspart versus the insulin secretagogue repaglinide, at the same glycemic control2009In: Acta Diabetologica, ISSN 0940-5429, E-ISSN 1432-5233, Vol. 46, no 1, p. 35-42Article in journal (Refereed)
    Abstract [en]

    Our aim was to study, at the same glycemic control, how treatment with either the insulin secretagogue repaglinide or exogenous insulin aspart affects endogenous insulin secretion, plasma insulin and IAPP (islet amyloid polypeptide) levels, GH-IGF (growth hormone-insulin-like growth factor) axis and plasma lipoprotein concentrations in patients with type 2 diabetes. Five patients, age 65.0 +/- A 4.1 years (mean +/- A SE), body weight 82.5 +/- A 5.0 kg, BMI (body mass index) 27.7 +/- A 1.5 kg/m(2) were treated for 10 weeks with repaglinide or insulin aspart in a randomized, cross-over study. At the end of each treatment a 24-h metabolic profile was performed. Blood glucose, C-peptide, free human insulin, free total (human and analogue) insulin, proinsulin, IAPP, IGF-I, IGFBP-1 (IGF binding protein-1), GHBP (growth hormone binding protein) and plasma lipoprotein concentrations were measured. Similar 24-h blood glucose profiles were obtained with repaglinide and insulin aspart treatment. During the repaglinide treatment, the meal related peaks of C-peptide and free human insulin were about twofold higher than during treatment with insulin aspart. Proinsulin, GHBP were higher and IAPP levels tended to be higher during repaglinide compared to insulin aspart. Postprandial plasma total cholesterol, triglycerides and apolipoprotein B concentrations were higher on repaglinide than on insulin aspart treatment. Our results show that, at the same glycemic control, treatment with exogenous insulin aspart in comparison with the insulin secretagogue repaglinide result in a lower endogenous insulin secretion, and a tendency towards a less atherogenic postprandial lipid profile.

  • 11.
    Dekker Nitert, Marloes
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
    Chisalitaa, Simona I.
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
    Olsson, Karolina
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
    Bornfeldt, Karin E.
    Department of Pathology, University of Washington School of Medicine, Seattle, USA.
    Arnqvist, Hans J.
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
    IGF-I/insulin hybrid receptors in human endothelial cells2005In: Molecular and Cellular Endocrinology, ISSN 0303-7207, E-ISSN 1872-8057, Vol. 229, no 1-2, p. 31-37Article in journal (Refereed)
    Abstract [en]

    Vascular complications are common in diabetes. IGF-I receptors (IGF-IR) and insulin receptors (IR) in endothelial cells might respond to altered levels of IGF-I and insulin, resulting in altered endothelial function in diabetes. We therefore studied IGF-IR and IR gene expression, ligand binding, receptor protein, and phosphorylation in human umbilical vein endothelial cells (HUVEC). IGF-IR mRNA was more abundant than IRmRNAin freshly isolatedHUVEC(IGF-IR/IR ratio 7.1±1.5) and in culturedHUVEC(ratio 3.5±0.51). Accordingly, specific binding of 125I-IGF-I (0.64±0.25%) was higher than that of 125I-insulin (0.25±0.09%). Protein was detected for both  eceptors and IGF-I/insulin hybrid receptors. IGF-IR phosphorylation was stimulated by 10−10 to 10−8M IGF-I. IR were activated by 10−9 to 10−8M insulin and IGF-I. We conclude that HUVEC express more IGF-IR than IR, and also express hybrid receptors. Both IGF-I and insulin phosphorylate their own receptors but only IGF-I seems to phosphorylate hybrid receptors.

  • 12.
    Johansson, Git
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
    Simona Chisalita, Ioana
    Linköping University, Department of Clinical and Experimental Medicine. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Local Health Care Services in Central Östergötland, Department of Acute Internal Medicine.
    Arnqvist, Hans
    Linköping University, Department of Clinical and Experimental Medicine. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Medicine, Department of Endocrinology and Gastroenterology UHL.
    Human microvascular endothelial cells are sensitive to IGF-I but resistant to insulin at the receptor level2008In: Molecular and Cellular Endocrinology, ISSN 0303-7207, E-ISSN 1872-8057, Vol. 296, no 1-2, p. 58-63Article in journal (Refereed)
    Abstract [en]

    Human microvascular endothelial cells (HMVEC) are sensitive to IGF-I but insulin resistant and express several times more IGF-I receptors (IGF-IR) than insulin receptors (IR). Our aim was to investigate the mechanism of this insulin resistance in cultured HMVEC by studying receptor activation and signal propagation downstream.

    propagation downstream. The IGF-IR β-subunit and the IR β-subunitwere detected and found to co-precipitate. IRAwas themajor IR isoformexpressed in HMVEC. IGF-I 10−9 to 10−8M phosphorylated its cognate receptor β-subunit. IGF- I also phosphorylated the IR β-subunit at 10−9 M. Phosphorylation of insulin receptor substrate 1 was obtained by IGF-I 10−9 to 10−8 M. Akt was phosphorylated by IGF-I at 10−8 to 10−7M and by insulin 10−7M. IGF-I at 10−8 to 10−6M significantly increased DNA-synthesis. We conclude that microvascular endothelial cells are sensitive to IGF-I but resistant to insulin due to a preponderance of IGF-I receptors and sequestration of insulin receptors into insulin/IGF-I hybrid receptors.

  • 13.
    Simona Chisalita, Ioana
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Surgery, Orthopedics and Oncology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Department of Endocrinology.
    Chong, Lee Ti
    Linköping University, Department of Clinical and Experimental Medicine, Division of Surgery, Orthopedics and Oncology. Linköping University, Faculty of Medicine and Health Sciences.
    Wajda, Maciej
    Linköping University, Department of Clinical and Experimental Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Local Health Care Services in Central Östergötland, Department of Emergency Medicine.
    Adolfsson, Lars
    Linköping University, Department of Clinical and Experimental Medicine, Division of Surgery, Orthopedics and Oncology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Orthopaedics in Linköping.
    Woisetschläger, Mischa
    Linköping University, Department of Medical and Health Sciences, Division of Radiological Sciences. Linköping University, Faculty of Medicine and Health Sciences.
    Spångeus, Anna
    Linköping University, Department of Medical and Health Sciences, Division of Cardiovascular Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Department of Endocrinology.
    Association of Insulin-like Growth Factor-1, Bone Mass and Inflammation to Low-energy Distal Radius Fractures and Fracture Healing in Elderly Women Attending Emergency Care2017In: ORTHOPAEDIC SURGERY, ISSN 1757-7853, Vol. 9, no 4, p. 380-385Article in journal (Refereed)
    Abstract [en]

    Objective

    Elderly patients suffer fractures through low-energy mechanisms. The distal radius is the most frequent fracture localization. Insulin-like growth factor-1 (IGF1) plays an important role in the maintenance of bone mass and its levels decline with advancing age and in states of malnutrition. Our aim was to investigate the association of IGF1 levels, bone mass, nutritional status, and inflammation to low-energy distal radius fractures and also study if fracture healing is influenced by IGF1, nutritional status, and inflammation.

    Methods

    Postmenopausal women, 55 years or older, with low-energy distal radius fractures occurring due to falling on slippery ground, indoors or outdoors, were recruited in the emergency department (ED) and followed 1 and 5 weeks after the initial trauma with biomarkers for nutritional status and inflammation. Fractures were diagnosed according to standard procedure by physical examination and X-ray. All patients were conservatively treated with plaster casts in the ED. Patients who needed interventions were excluded from our study. Fracture healing was evaluated from radiographs. Fracture healing assessment was made with a five-point scale where the radiological assessment included callus formation, fracture line, and stage of union. Blood samples were taken within 24 h after fracture and analyzed in the routine laboratory. Bone mineral density (BMD) was measured by dual-energy X-ray absorptiometry (DXA).

    Results

    Thirty-eight Caucasian women, aged 70.5 8.9 years (mean +/- SD) old, were recruited. Nutritional status, as evaluated by albumin (40.3 +/- 3.1 g/L), IGF1 (125.3 +/- 39.9 g/L), body mass index (26.9 +/- 3.6 kg/m(2)), arm diameter (28.9 +/- 8.9 cm), and arm skinfold (2.5 +/- 0.7 cm), was normal. A positive correlation was found between IGF1 at visit 1 and the lowest BMD for hip, spine, or radius (r = 0.39, P = 0.04). High sensitive C-reactive protein (hsCRP) and leukocytes were higher at the fracture event compared to 5 weeks later (P = 0.07 and P amp;lt; 0.001, respectively). Fracture healing parameters (i.e. callus formation, fracture line, and stage of union) were positively correlated with the initial leukocyte count and to difference in thrombocyte count between visit 1 and 3.

    Conclusions

    In elderly women with low-energy distal radius fractures, an association between IGF1 and lowest measures of BMD was found, indicating that low IGF1 could be an indirect risk factor for fractures. Fracture healing was associated with initial leukocytosis and a lower thrombocyte count, suggesting that inflammation and thrombocytes are important components in fracture healing.

  • 14.
    Simona Chisalita, Ioana
    et al.
    Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Department of Endocrinology. Linköping University, Department of Medical and Health Sciences, Division of Cardiovascular Medicine.
    Ludvigsson, Johnny
    Linköping University, Department of Clinical and Experimental Medicine, Division of Children's and Women's health. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center of Paediatrics and Gynaecology and Obstetrics, H.K.H. Kronprinsessan Victorias barn- och ungdomssjukhus.
    Insulin-Like Growth Factor-1 at Diagnosis and during Subsequent Years in Adolescents with Type 1 Diabetes2018In: Journal of Diabetes Research, ISSN 2314-6745, E-ISSN 2314-6753, article id 8623560Article in journal (Refereed)
    Abstract [en]

    Background. Type 1 diabetes (T1D) in adolescents is associated with alterations in the insulin-like factor system probably caused both by a deranged metabolism and insulinopenia in the portal vein.

    Objective. To study how the circulating IGF-1 is affected at diagnosis and during subsequent years in adolescents with T1D.

    Methods. Ten girls and ten boys with type 1 diabetes (T1D), aged 13.0 +/- 1.4 (mean +/- SD) years at diagnosis, took part in the study. Blood samples were drawn at diagnosis and after 3, 9, 18, and 48 months. HbA1c, total IGF-1, and C-peptide were measured.

    Results. At diagnosis, the patients had high HbA1c, low IGF-1, and measurable C-peptide. After the start of insulin treatment, maximal improvement in glycemic control and IGF-1 occurred within 3 months and then both tended to deteriorate, that is, HbA1c to increase and IGF-1 to decrease. C-peptide decreased with time, and after 4 years, half of the patients were C-peptide negative. At diagnosis, C-peptide correlated positively to IGF-1 (r = 0 50; p amp;lt; 0 03). C-peptide correlated negatively with insulin dose (U/kg) after 18 and 48 months from diagnosis (r = -0 48; p amp;lt; 0 03 and r = -0 72; p amp;lt; 0 001, resp.).

    Conclusions. In conclusion, our results show that in newly diagnosed adolescents with type 1 diabetes and deranged metabolism, the IGF-1 level is low and rapidly improves with insulin treatment but later tends to decrease concomitantly with declining endogenous insulin secretion.

  • 15. Söderlund, Gustav
    et al.
    Haarhaus, Mathias
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Medicine and Care, Nephrology. Östergötlands Läns Landsting, Centre for Medicine, Department of Nephrology UHL.
    Chisalita, Ioana Simona
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Biomedicine and Surgery, Division of cell biology.
    Arnqvist, Hans
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Biomedicine and Surgery, Division of cell biology. Östergötlands Läns Landsting, Centre for Medicine, Department of Endocrinology and Gastroenterology UHL.
    Inhibition of puromycin-induced apoptosis in breast cancer cells by IGF-I occurs simultaneously with increased protein synthesis2004In: Neoplasma (Bratislava), ISSN 0028-2685, E-ISSN 1338-4317, Vol. 51, no 1Article in journal (Refereed)
    Abstract [en]

    The objective of the following work was to study the apoptosis inducing effect of puromycin in MCF-7 breast cancer cells and compare this effect with cycloheximide and emetine, 2 other inhibitors of protein synthesis. We also wished to investigate if the apoptosis modulating effect of insulin-like growth factor-1 (IGF-I) was similar for the 3 inhibitors. An immunological assay, quantifying mono- and oligonucleosome fragments and morphological criteria after nuclear staining, were used to study apoptosis. Protein synthesis was measured by incorporation of 3H-leucine in the cells, and solution hybridization and Western blot were performed to estimate IGF-I receptor m-RNA and IGF-I receptor protein respectively. Puromycin at 0.5 μg/ml induced a high level of apoptosis in MCF-7 breast cancer cells, although there was still a non-negligible amount of synthesized protein. In the case of cycloheximide and emetine, apoptosis occured when protein synthesis was almost completely blocked. IGF-I at a concentration of 10 ng/ml significantly reduced the level of apoptosis induced by puromycin, emetine, or cycloheximide. We also noticed a parallel increase in 3H-leucine incorporation when apoptosis induced by puromycin was lowered as an effect of IGF-I, in contrast to cycloheximide and emetine where IGF-I reduced the apoptosis level without increasing the 3H-leucine incorporation. At a higher concentration of puromycin (5. 7 μg/ml), which blocked protein synthesis, IGF-I at 10 ng/ml did not reduce apoptosis. The level of IGF-I receptor m-RNA was not influenced by the use of a concentration of puromycin (0.5 μg/ml) inducing a high degree of apoptosis. These results suggest, that reduction of puromycin-induced apoptosis by IGF-I occurs simultaneously with increased protein synthesis, in contrast to emetine and cycloheximide. Furthermore it would appear that puromycin-induced apoptosis is not caused by reduced levels of IGF-I receptors.

  • 16.
    Van dijk, Peter R
    et al.
    Isala, Diabetes Centre, Zwolle, The Netherlands.
    Logtenberg, Susan J J
    University Medical Center Groningen, The Netherlands.
    Chisalita, Ioana Simona
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Local Health Care Services in Central Östergötland, Department of Emergency Medicine.
    Hedman, Christina A.
    Linköping University, Department of Medical and Health Sciences, Division of Cardiovascular Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Department of Endocrinology.
    Groenier, Klaas H
    University Medical Center Groningen, The Netherlands.
    Gans, Reinold O B
    University Medical Center Groningen, The Netherlands.
    Kleefstra, Nanne
    University Medical Center Groningen, The Netherlands.
    Arnqvist, Hans J.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Department of Endocrinology.
    Bilo, Henk J G
    University Medical Center Groningen, The Netherlands.
    After 6years of intraperitoneal insulin administration IGF-I concentrations in T1DM patients are at low-normal level.2015In: Growth Hormone & IGF Research, ISSN 1096-6374, E-ISSN 1532-2238, Vol. 25, no 6, p. 316-319Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE: Low concentrations of insulin-like growth factor-I (IGFI) have been reported in type 1 diabetes mellitus (T1DM), suggested to be due to low insulin concentrations in the portal vein. The aim was to describe the long-term course of IGFI concentrations among T1DM subjects treated with continuous intraperitoneal (IP) insulin infusion (CIPII).

    DESIGN: Nineteen patients that participated in a randomized cross-over trial comparing CIPII and subcutaneous (SC) insulin therapy in 2006 were followed until 2012. IGF-I measurements were performed at the start of the 2006 study, after the 6month SC- and CIPII treatment phase in 2006 and during CIPII therapy in 2012. Z-scores were calculated to compare the IGF-I concentrations with age-specific normative range values of a non-DM reference population.

    RESULTS: In 2012, IGF-I Z-scores (-0.7; 95% confidence interval -1.3, -0.2) were significantly higher than at the start of the 2006 study (-2.5; -3.3, -1.8), the end of the SC (-2.0; -2.6, -1.5) and CIPII (-1.6; -2.1, -1.0) treatment phase with a mean difference of: 1.8 (0.9, 2.7), 1.3 (0.5, 2.1) and 0.8 (0.1, 1.6), respectively.

    CONCLUSION: After 6years of treatment with CIPII, IGF-I concentrations among T1DM patients increased to a level that is higher than during prior SC insulin treatment and is in the lower normal range compared to a non-DM reference population. The results of this study suggest that long-term IP insulin administration influences the IGF system in T1DM.

  • 17.
    van Dijk, Peter R.
    et al.
    Isala, Netherlands.
    Logtenberg, Susan J. J.
    Isala, Netherlands; Diakonessen Hospital, Netherlands.
    Chisalita, Ioana Simona
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Region Östergötland, Local Health Care Services in Central Östergötland, Department of Emergency Medicine. Linköping University, Faculty of Medicine and Health Sciences.
    Hedman, Christina
    Region Östergötland, Heart and Medicine Center, Department of Endocrinology. Linköping University, Faculty of Medicine and Health Sciences. Linköping University, Department of Medical and Health Sciences, Division of Cardiovascular Medicine.
    Groenier, Klaas H.
    Isala, Netherlands; University of Groningen, Netherlands.
    Gans, Reinold O. B.
    University of Groningen, Netherlands.
    Kleefstra, Nanne
    Isala, Netherlands; University of Groningen, Netherlands; Langerhans Medical Research Grp, Netherlands.
    Arnqvist, Hans
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Department of Endocrinology.
    Bilo, Henk J. G.
    Isala, Netherlands; Isala, Netherlands; University of Groningen, Netherlands.
    Different Effects of Intraperitoneal and Subcutaneous Insulin Administration on the GH-IGF-1 Axis in Type 1 Diabetes2016In: Journal of Clinical Endocrinology and Metabolism, ISSN 0021-972X, E-ISSN 1945-7197, Vol. 101, no 6, p. 2493-2501Article in journal (Refereed)
    Abstract [en]

    Context: In type 1 diabetes mellitus, low levels of insulin-like growth factor -1 (IGF-1) and IGF binding protein-3 (IGFBP-3) and high levels of GH and IGFBP-1 are present, probably due to portal vein insulinopenia. Objective: To test the hypothesis that continuous ip insulin infusion (CIPII) has a more pronounced effect than sc insulin therapy on regulation of the GH-IGF-1 axis. Design: This was a prospective, observational case-control study. Measurements were performed twice at a 26-week interval. Setting: Two secondary care hospitals in the Netherlands participated in the study. Patients: There were a total of 184 patients, age-and gender-matched, of which 39 used CIPII and 145 sc insulin therapy for the past 4 years. Outcomes: Primary endpoint included differences in IGF-1. Secondary outcomes were differences in GH, IGFBP-1, and IGFBP-3. Results: IGF-1 was higher with CIPII as compared to SC insulin therapy: 124 mu g/liter (95% confidence interval [CI], 111-138) vs 108 mu g/liter (95% CI 102-115) (P = .035). Additionally, IGFBP-3 concentrations were higher and IGFBP-1 and GH concentrations were lower with CIPII as compared to SC insulin therapy: 3.78 mg/liter (95% CI, 3.49 - 4.10) vs 3.31 mg/liter (95% CI, 3.173.47) for IGFBP-3, 50.9 mu g/liter (95% CI, 37.9 - 68.2) vs 102.6 mu g/liter (95% CI, 87.8 - 119.8) for IGFBP-1 and 0.68 mu g/liter (95% CI, 0.44 - 1.06) vs 1.21 mu g/liter (95% CI, 0.95-1.54) for GH, respectively. In multivariate analysis, IGF-1 had no significant association with HbA1c. Conclusions: The GH-IGF-1 axis may be affected by the route of insulin administration with CIPII counteracting dysregulation of the GH-IGF1 axis present during sc insulin therapy.

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