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Simona Chisalita, Ioana
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Publications (10 of 17) Show all publications
Simona Chisalita, I. & Ludvigsson, J. (2018). Insulin-Like Growth Factor-1 at Diagnosis and during Subsequent Years in Adolescents with Type 1 Diabetes. Journal of Diabetes Research, Article ID 8623560.
Open this publication in new window or tab >>Insulin-Like Growth Factor-1 at Diagnosis and during Subsequent Years in Adolescents with Type 1 Diabetes
2018 (English)In: Journal of Diabetes Research, ISSN 2314-6745, E-ISSN 2314-6753, article id 8623560Article in journal (Refereed) Published
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.

Place, publisher, year, edition, pages
Hindawi Publishing Corporation, 2018
National Category
Endocrinology and Diabetes
Identifiers
urn:nbn:se:liu:diva-147455 (URN)10.1155/2018/8623560 (DOI)000428896300001 ()29744370 (PubMedID)
Note

Funding Agencies|Landstinget Ostergotland; Swedish Medical Research Council [04952]

Available from: 2018-05-16 Created: 2018-05-16 Last updated: 2018-06-04Bibliographically approved
Simona Chisalita, I., Chong, L. T., Wajda, M., Adolfsson, L., Woisetschläger, M. & Spångeus, A. (2017). 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 Care. ORTHOPAEDIC SURGERY, 9(4), 380-385
Open this publication in new window or tab >>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 Care
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2017 (English)In: ORTHOPAEDIC SURGERY, ISSN 1757-7853, Vol. 9, no 4, p. 380-385Article in journal (Refereed) Published
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.

Place, publisher, year, edition, pages
Wiley-Blackwell, 2017
Keywords
Fracture healing; Inflammation; Insulin-like growth factor-1; Radius fracture
National Category
Forensic Science
Identifiers
urn:nbn:se:liu:diva-143640 (URN)10.1111/os.12358 (DOI)000416242400007 ()29178313 (PubMedID)2-s2.0-85035025188 (Scopus ID)
Available from: 2017-12-13 Created: 2017-12-13 Last updated: 2018-04-18Bibliographically approved
van Dijk, P. R., Logtenberg, S. J. J., Chisalita, I. S., Hedman, C., Groenier, K. H., Gans, R. O. B., . . . Bilo, H. J. G. (2016). Different Effects of Intraperitoneal and Subcutaneous Insulin Administration on the GH-IGF-1 Axis in Type 1 Diabetes. Journal of Clinical Endocrinology and Metabolism, 101(6), 2493-2501
Open this publication in new window or tab >>Different Effects of Intraperitoneal and Subcutaneous Insulin Administration on the GH-IGF-1 Axis in Type 1 Diabetes
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2016 (English)In: Journal of Clinical Endocrinology and Metabolism, ISSN 0021-972X, E-ISSN 1945-7197, Vol. 101, no 6, p. 2493-2501Article in journal (Refereed) Published
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.

Place, publisher, year, edition, pages
ENDOCRINE SOC, 2016
National Category
Endocrinology and Diabetes
Identifiers
urn:nbn:se:liu:diva-130291 (URN)10.1210/jc.2016-1473 (DOI)000378821100026 ()27115061 (PubMedID)
Note

Funding Agencies|Zwols Wetenschapsfonds Isala Klinieken; Sanofi-Aventis The Netherlands B.V.

Available from: 2016-07-31 Created: 2016-07-28 Last updated: 2017-04-24
Van dijk, P. R., Logtenberg, S. J., Chisalita, I. S., Hedman, C. A., Groenier, K. H., Gans, R. O., . . . Bilo, H. J. (2015). After 6years of intraperitoneal insulin administration IGF-I concentrations in T1DM patients are at low-normal level.. Growth Hormone & IGF Research, 25(6), 316-319
Open this publication in new window or tab >>After 6years of intraperitoneal insulin administration IGF-I concentrations in T1DM patients are at low-normal level.
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2015 (English)In: Growth Hormone & IGF Research, ISSN 1096-6374, E-ISSN 1532-2238, Vol. 25, no 6, p. 316-319Article in journal (Refereed) Published
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.

Keywords
IGF-I; Intraperitoneal insulin; Type 1 diabetes mellitus
National Category
Endocrinology and Diabetes Physiology
Identifiers
urn:nbn:se:liu:diva-124061 (URN)10.1016/j.ghir.2015.08.007 (DOI)000366962800009 ()26336814 (PubMedID)
Note

Funding agencies: Medical Research Council of Southeast Sweden (FORSS); Stichting Zwols Wetenschapsfonds Isala Klinieken (ZWIK)

Available from: 2016-01-19 Created: 2016-01-19 Last updated: 2018-01-10
Chisalita, I. S., Dahlström, U., Arnqvist, H. & Alehagen, U. (2014). Proinsulin and IGFBP-1 predicts mortality in an elderly population. International Journal of Cardiology, 174(2), 260-267
Open this publication in new window or tab >>Proinsulin and IGFBP-1 predicts mortality in an elderly population
2014 (English)In: International Journal of Cardiology, ISSN 0167-5273, E-ISSN 1874-1754, Vol. 174, no 2, p. 260-267Article in journal (Refereed) Published
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.

Place, publisher, year, edition, pages
Elsevier, 2014
Keywords
Insulin-like growth factor binding protein-1, Proinsulin, Insulin, Elderly population
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-108157 (URN)10.1016/j.ijcard.2014.03.171 (DOI)000336528000029 ()24794551 (PubMedID)
Available from: 2014-06-26 Created: 2014-06-26 Last updated: 2017-12-05Bibliographically approved
Bäck, K., Islam, R., Johansson, G., Chisalita, I. S. & Arnqvist, H. (2012). Insulin and IGF1 receptors in human cardiac microvascular endothelial cells: metabolic, mitogenic and anti-inflammatory effects. Journal of Endocrinology, 215(1), 89-96
Open this publication in new window or tab >>Insulin and IGF1 receptors in human cardiac microvascular endothelial cells: metabolic, mitogenic and anti-inflammatory effects
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2012 (English)In: Journal of Endocrinology, ISSN 0022-0795, E-ISSN 1479-6805, Vol. 215, no 1, p. 89-96Article in journal (Refereed) Published
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.

Place, publisher, year, edition, pages
Society for Endocrinology, 2012
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-86558 (URN)10.1530/JOE-12-0261 (DOI)000309000000010 ()
Available from: 2012-12-19 Created: 2012-12-19 Last updated: 2017-12-06
Chisalita, I. S., Dahlström, U., Arnqvist, H. & Alehagen, U. (2011). Increased IGF1 levels in relation to heart failure and cardiovascular mortality in an elderly population: impact of ACE inhibitors. European Journal of Endocrinology, 165(6), 891-898
Open this publication in new window or tab >>Increased IGF1 levels in relation to heart failure and cardiovascular mortality in an elderly population: impact of ACE inhibitors
2011 (English)In: European Journal of Endocrinology, ISSN 0804-4643, E-ISSN 1479-683X, Vol. 165, no 6, p. 891-898Article in journal (Refereed) Published
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.

Place, publisher, year, edition, pages
European Society of Endocrinology, 2011
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-73322 (URN)10.1530/EJE-11-0584 (DOI)000297687900007 ()
Available from: 2012-01-03 Created: 2012-01-02 Last updated: 2017-12-08
Chisalita, S. I., Lindström, T., Eson Jennersjö, P., Paulsson, J., Westermark, G., Olsson, A. & Arnqvist, H. (2009). Differential lipid profile and hormonal response in type 2 diabetes by exogenous insulin aspart versus the insulin secretagogue repaglinide, at the same glycemic control. Acta Diabetologica, 46(1), 35-42
Open this publication in new window or tab >>Differential lipid profile and hormonal response in type 2 diabetes by exogenous insulin aspart versus the insulin secretagogue repaglinide, at the same glycemic control
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2009 (English)In: Acta Diabetologica, ISSN 0940-5429, E-ISSN 1432-5233, Vol. 46, no 1, p. 35-42Article in journal (Refereed) Published
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.

Keywords
Insulin secretagogue, Insulin-like growth factor, Lipoprotein
National Category
Endocrinology and Diabetes
Identifiers
urn:nbn:se:liu:diva-16891 (URN)10.1007/s00592-008-0055-6 (DOI)000263001000005 ()
Note

The original publication is available at www.springerlink.com: Ioana Simona Chisalita, Torbjörn Lindström, Pär Eson Jennersjö, Johan Paulsson, Gunilla Westermark, Anders Olsson and Hans Arnqvist, Differential lipid profile and hormonal response in type 2 diabetes by exogenous insulin aspart versus the insulin secretagogue repaglinide, at the same glycemic control, 2009, ACTA DIABETOLOGICA, (46), 1, 35-42. http://dx.doi.org/10.1007/s00592-008-0055-6 Copyright: Springer -- Verlag http://www.springerlink.com/

Available from: 2009-02-26 Created: 2009-02-20 Last updated: 2017-12-13Bibliographically approved
Chisalita, I. S., Johansson, G., Liefvendahl, E., Bäck, K. & Arnqvist, H. (2009). Human aortic smooth muscle cells are insulin resistant at the receptor level but sensitive to IGF1 and IGF2. Journal of Molecular Endocrinology, 43(5-6), 231-239
Open this publication in new window or tab >>Human aortic smooth muscle cells are insulin resistant at the receptor level but sensitive to IGF1 and IGF2
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2009 (English)In: Journal of Molecular Endocrinology, ISSN 0952-5041, E-ISSN 1479-6813, Vol. 43, no 5-6, p. 231-239Article in journal (Refereed) Published
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.

Keywords
Receptors, insulin, IGF-I, IGF-II, IRS-1, Erk 1/2, Akt, DNA-synthesis, glucose accumulation.
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-19283 (URN)10.1677/JME-09-0021 (DOI)
Available from: 2009-06-16 Created: 2009-06-16 Last updated: 2017-12-13Bibliographically approved
Chisalita, S. I. (2008). Expression and function of IGF-I and insulin receptors in human micro- and macrovascular cells. (Doctoral dissertation). Linköping: Linköping University Electronic Press
Open this publication in new window or tab >>Expression and function of IGF-I and insulin receptors in human micro- and macrovascular cells
2008 (English)Doctoral 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.

Place, publisher, year, edition, pages
Linköping: Linköping University Electronic Press, 2008. p. 89
Series
Linköping University Medical Dissertations, ISSN 0345-0082 ; 1045
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-12558 (URN)978-91-7393-972-0 (ISBN)
Public defence
2008-03-14, Berzeliussalen (hus 463, ingång 65), Hälsouniversitet, Campus US, Linköpings universitet, Linköping, 09:00 (Swedish)
Opponent
Supervisors
Available from: 2008-09-15 Created: 2008-09-15 Last updated: 2009-08-21Bibliographically approved
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