liu.seSearch for publications in DiVA
Change search
CiteExportLink to record
Permanent link

Direct link
Cite
Citation style
  • apa
  • harvard1
  • ieee
  • modern-language-association-8th-edition
  • vancouver
  • oxford
  • Other style
More styles
Language
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Other locale
More languages
Output format
  • html
  • text
  • asciidoc
  • rtf
Interaction between insulin and IGF-I receptors in insulin sensitive and insulin resistant cells and tissues
Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences. (Hans Arnqvist)
2011 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Insulin and insulin-like growth factor I (IGF-I) are two related peptides with similar structure. They mediate their effects by binding to their respective receptor, the insulin receptor (IR) and the IGF-I receptor (IGF-IR) and induce intracellular signalling cascades resulting in metabolic or mitogenic effects. The relative abundance of IR and IGF-IR is of importance for the type of effect that is the outcome of the signal. There are few studies investigating the relative receptor abundance and its effects in human cells and tissues.

In this thesis we wanted to study abundance and regulation of insulin and IGF-I receptors in different human cells and tissues and examine the effects of variations in insulin and IGF-I receptor abundance between different cells and tissues.

We examined IR and IGF-IR gene and protein expression and the effects of insulin and IGF-I on receptor phosphorylation, DNA synthesis and glucose transport.

Our results show that there is a large variation in the distribution of IR and IGF-IR in different human cells and tissues. Renal artery intima-media expressed predominantly IGF-IR while in liver IR was the predominant receptor type.

Differentiation of human preadipocytes results in a change in relative expression of IGF-IR to IR. Mature adipocytes express almost 10-fold more IR than IGF-IR while preadipocytes express almost the same amounts of both receptors. Mature tissues, such as liver, skeletal muscle, myometrium and renal artery intima-media, express predominantly IR-B. Preadipocytes express IR-A and the expression of IR-B is induced during differentiation.

We could show the presence of insulin/IGF-I hybrid receptors in preadipocytes but not in mature adipocytes. Cultured endothelial cells express mostly IGF-IR and insulin/IGF-I hybrid receptors and these cells respond mainly to IGF-I. Due to the large abundance of IR mature adipocytes are sensitive to insulin but insensitive to IGF-I whereas preadipocytes expressing equal amounts of both receptors respond to both insulin and IGF-I. Insulin and IGF-I are only partial agonists to each other’s receptors in human preadipocytes and adipocytes.

The overall results indicate that differential expression of IGF-IR and IR is a key mechanism in regulation of growth and metabolism.

Place, publisher, year, edition, pages
Linköping: Linköping University Electronic Press , 2011. , 46 p.
Series
Linköping University Medical Dissertations, ISSN 0345-0082 ; 1268
National Category
Medical and Health Sciences
Identifiers
URN: urn:nbn:se:liu:diva-71892ISBN: 978-91-7393-042-0 (print)OAI: oai:DiVA.org:liu-71892DiVA: diva2:455222
Public defence
2011-12-09, Berzeliussalen, hus 463, ingång 65, Campus US, Linköpings universitet, Linköping, 09:00 (Swedish)
Opponent
Supervisors
Available from: 2011-11-09 Created: 2011-11-09 Last updated: 2011-11-09Bibliographically approved
List of papers
1. Changes in insulin and IGF-I receptor expression during differentiation of human preadipocytes
Open this publication in new window or tab >>Changes in insulin and IGF-I receptor expression during differentiation of human preadipocytes
2009 (English)In: Growth Hormone & IGF Research, ISSN 1096-6374, Vol. 19, no 2, 101-111 p.Article in journal (Refereed) Published
Abstract [en]

Mature adipocytes originate from fibroblast-like precursor cells, preadipocytes, which differentiate to obtain the characteristics of adipocytes. Our aim was to investigate how differentiation of human preadipocytes affects the distribution of insulin receptors (IR) and IGF-I receptors (IGF-IR) and other cell characteristics. Preadipocytes were differentiated using indomethacine, dexamethasone, isobutyl-methylxantine (IBMX) and high concentration of insulin. Gene expression was quantified by real-time RT-PCT in preadipocytes (PA), differentiated preadipocytes (dPA) and mature adipocytes (mAD). The amount of expressed receptor protein was analyzed using receptor specific ELISAs and Western blot. We also studied DNA synthesis with radiolabeled thymidine incorporation and glucose accumulation with radiolabeled glucose. Differentiation of PA increased gene expression of IR but not IGF-IR, GLUT4, growth hormone receptor (GHR) and adiponectin appeared or increased. In PA and dPA only IR-A was expressed whereas also IR-B was detected in mAD. By Western blot and ELISA, IR and IGF-IR was phosphorylated by their own ligant at 1 nM and in dPA the acitivation of both receptors was stimulated by IGF-I, but not insulin, at 1 nM. Accumulation of glucose in PA was increased by insulin at 10 nM and by IGF-I at 1 nM and 10 nM. DNA synthesis was increased by insulin and IGF-I at 10 nM.

In conclusion, both IR and IGF-IR are present in human preadipocytes and adipocytes. Differentiation is characterized by an increased IR/IGF-IR ratio.

Keyword
Insulin receptor isoforms, Cell metabolism, Growth factors
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-17895 (URN)10.1016/j.ghir.2008.06.004 (DOI)
Note
Original Publication: Karolina Bäck and Hans Arnqvist, Changes in insulin and IGF-I receptor expression during differentiation of human preadipocytes, 2009, GROWTH HORMONE and IGF RESEARCH, (19), 2, 101-111. http://dx.doi.org/10.1016/j.ghir.2008.06.004 Copyright: Elsevier Science B.V., Amsterdam http://www.elsevier.com/ Available from: 2009-05-20 Created: 2009-04-24 Last updated: 2011-11-09Bibliographically approved
2. Differential effects of IGF-I, IGF-II and insulin in human preadipocytes and adipocytes - Role of insulin and IGF-I receptors
Open this publication in new window or tab >>Differential effects of IGF-I, IGF-II and insulin in human preadipocytes and adipocytes - Role of insulin and IGF-I receptors
2011 (English)In: Molecular and Cellular Endocrinology, ISSN 0303-7207, E-ISSN 1872-8057, Vol. 339, no 02-jan, 130-135 p.Article in journal (Refereed) Published
Abstract [en]

We compared insulin and IGF effects in adipocytes expressing IR (insulin receptors), and preadipocytes expressing IR and IGF-IR (IGF-I receptors). Treatment of adipocytes with insulin, IGF-II or IGF-I resulted in phosphorylation of IR. Order of potency was insulin greater thanIGF-IIgreater than IGF-I. In preadipocytes IR, IGF-IR and insulin/IGF-I hybrid receptors (HR) were detected. Treatment of preadipocytes with IGF-I and IGF-II 10(-8) M resulted in activation of IGF-IR and IR whereas insulin was more potent in activating IR, with no effect on IGF-IR. In adipocytes glucose transport was 100-fold more sensitive to insulin than to IGFs and the maximal effect was higher with insulin. In preadipocytes glucose accumulation and DNA synthesis was equally sensitive to insulin and IGFs but the maximal effect was higher with IGF-I. In conclusion, insulin and IGF-I activate their cognate receptors and IGF-I also HR. IGF-II activates IR, IGF-IR and HR. Insulin and IGF-I are partial agonists to each others receptors.

Place, publisher, year, edition, pages
Elsevier Science B.V., Amsterdam., 2011
Keyword
Growth factors; Hybrid receptors; Receptor activation; DNA synthesis; Glucose metabolism
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-69862 (URN)10.1016/j.mce.2011.04.005 (DOI)000292580100016 ()
Available from: 2011-08-10 Created: 2011-08-08 Last updated: 2017-12-08
3. Role of insulin and IGF-I receptors in human cardiac microvascular endothelial cells; metabolic, mitogenic and anti-inflammatory effects
Open this publication in new window or tab >>Role of insulin and IGF-I receptors in human cardiac microvascular endothelial cells; metabolic, mitogenic and anti-inflammatory effects
Show others...
(English)Manuscript (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.

Keyword
receptor ELISA, thymidine incorporation, glucose accumulation, E-selectin expression
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-71890 (URN)
Available from: 2011-11-09 Created: 2011-11-09 Last updated: 2011-11-09Bibliographically approved
4. Differential expression of insulin and IGF-I receptors in human tissues
Open this publication in new window or tab >>Differential expression of insulin and IGF-I receptors in human tissues
Show others...
(English)Manuscript (preprint) (Other academic)
Abstract [en]

Insulin and IGF-I are related peptides with similar structure. They both signal via their cognate receptors, the insulin receptor (IR) and the insulin-like growth factor (IGF)-I receptor (IGF-IR).

Our aim was to simultaneously measure the amount of insulin and IGF-I receptors in different human tissues and also the IR-A and IR-B isoforms to study tissue specific expression

Renal artery intima-media, myometrium, skeletal muscle or liver tissue samples were obtained from patients undergoing surgery. IR, IGF-IR, IR-A and IR-B gene expression was investigated with real-time RT-PCR and expression of IR and IGF-IR protein was examined by Western blot and ELISA.

Renal arteries and myometrium expressed the IGF-IR gene to a higher extent than the IR gene, liver expressed more IR than IGF-IR and skeletal muscle expressed almost equal amounts of both receptors. IR-B was the most abundant isoform in all tissues. With Western blot we could detect IR in skeletal muscle, liver and myometrium. With ELISA we found that, normalized to total protein, the highest levels of IGF-IR were found in renal arteries and myometrium and low levels in skeletal muscle and liver. The highest levels of IR were found in liver.

In conclusion there is a large variation in the quantity and ratio of insulin receptors and IGF-I receptors expressed in different tissues, the extremes being arterial intima media with predominantly IGF-I receptors and liver with predominantly insulin receptors. This suggests that differential expression of insulin and IGF-I receptors is a key mechanism in regulation of growth and metabolism.

Keyword
liver, skeletal muscle, myometrium, renal artery intima-media
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-71891 (URN)
Available from: 2011-11-09 Created: 2011-11-09 Last updated: 2011-11-09Bibliographically approved

Open Access in DiVA

Interaction between insulin and IGF-I receptors in insulin sensitive and insulin resistant cells and tissues(1214 kB)1989 downloads
File information
File name FULLTEXT01.pdfFile size 1214 kBChecksum SHA-512
5623752db7e2d9d38118214f9b63f8281bc1c71ada14e3718498dc652cb07f6d92be409a9ecbef05d3bc5267947d0c6becdeabe060aae45a9beb3d46d7a32d29
Type fulltextMimetype application/pdf
omslag(132 kB)30 downloads
File information
File name COVER01.pdfFile size 132 kBChecksum SHA-512
657f98e28846d472255da78718ac346451d7d203488fab787052e2de362b71a6bd157849ca030f982caec09c124ea233f812f300bdc33417294291f66261498d
Type coverMimetype application/pdf

Authority records BETA

Bäck, Karolina

Search in DiVA

By author/editor
Bäck, Karolina
By organisation
Cell BiologyFaculty of Health Sciences
Medical and Health Sciences

Search outside of DiVA

GoogleGoogle Scholar
Total: 1989 downloads
The number of downloads is the sum of all downloads of full texts. It may include eg previous versions that are now no longer available

isbn
urn-nbn

Altmetric score

isbn
urn-nbn
Total: 601 hits
CiteExportLink to record
Permanent link

Direct link
Cite
Citation style
  • apa
  • harvard1
  • ieee
  • modern-language-association-8th-edition
  • vancouver
  • oxford
  • Other style
More styles
Language
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Other locale
More languages
Output format
  • html
  • text
  • asciidoc
  • rtf