Insulin receptor isoforms as targets
Insulin sends signals to cells via two receptors
Insulin has many functions in the body and affects the activity of most cells. To initiate specific molecular processes in a cell, insulin binds to one of its two receptors, IR-A and IR-B, embedded in the cell membrane.
Signaling via IR-A and IR-B leads to distinct molecular events
In the pancreatic beta-cell for example, binding of insulin to IR-A initiates a chain of molecular events resulting in insulin production. On the other hand, binding of insulin to IR-B increases the production of glucokinase, the glucose sensor of the beta-cell.
Different tissues have different amounts of IR-A and IR-B
Almost every cell in the body has both IR-A and IR-B embedded in its plasma membrane. Typical insulin targets tissues like fat, muscle and liver cells have predominantly IR-B. Cancer cells, on the other hand, have mostly IR-A.
Platform for screening substances that selectively inhibit or activate insulin receptors
Biocrine has developed a set of tools facilitating efficient and precise screening of compounds that selectively activate or inhibit signalling via either IR-A or IR-B. In a fluorescent microscope, activation of IR-A versus IR-B can be detected by an increase in red versus green fluorescence, respectively.
.Mechanistic understanding of insulin receptor modulation: Implications for the development of anti-diabetic drugs.
Read more about insulin receptor isoforms:
- Insulin-feedback via PI3K-C2α activated PKBα/Akt1 is required for glucose-stimulated insulin secretion. Leibiger B et.al.FASEB J. 2010 Jun;24(6):1824-37
- Novel aspects on pancreatic beta-cell signal-transduction. Leibiger I et al. Biochem Biophys Res Commun. 2010 May 21;396(1):111-5
- Insulin Signaling in the Pancreatic β-Cell. Leibiger I et al. Annu Rev Nutr. 2008;28:233-51
- Selective gene activation by spatial segregation of insulin receptor B signaling. Uhles S et al. FASEB J. 2007 May;21(7):1609-21
- Isoform-specific insulin receptor signaling involves different plasma membrane domains. Uhles S, et al., J Cell Biol. 2003 Dec 22;163(6):1327-37
- Insulin feedback action on pancreatic beta-cell function. Leibiger I et al. FEBS Lett. 2002 Dec 4;532(1-2):1-6
- Selective insulin signaling through A and B insulin receptors regulates transcription of insulin and glucokinase genes in pancreatic beta cells. Leibiger B, et al., Mol Cell. 2001 Mar;7(3):559-70
- Glucose-stimulated insulin biosynthesis depends on insulin-stimulated insulin gene transcription. Leibiger B et.al. J Biol Chem. 2000 Sep 29;275(39):30153-6
- Exocytosis of insulin promotes insulin gene transcription via the insulin receptor/PI-3 kinase/p70 s6 kinase and CaM kinase pathways. Leibiger I et.al. Mol Cell. 1998 May;1(6):933-8
- Diet-induced β-cell insulin resistance results in reversible loss of functional β-cell mass. Paschen M et al. FASEB J. 2019 Jan;33(1):204-218.
- Mechanistic understanding of insulin receptor modulation: Implications for the development of anti-diabetic drugs. Yunn NO et al. Pharmacol Ther. 2018 May;185:86-98.
- Intraocular in vivo imaging of pancreatic islet cell physiology/pathology. Leibiger IB et al. Mol Metab. 2017 May 4;6(9):1002-1009.
- Non-invasive cell type selective in vivo monitoring of insulin resistance dynamics. Paschen M et al. Sci Rep. 2016 Feb 22;6:21448.
- Nephrin Contributes to Insulin Secretion and Affects Mammalian Target of Rapamycin Signaling Independently of Insulin Receptor. Villarreal R et al. J Am Soc Nephrol. 2016 Aår;27(4):1029-41.
- PI3K-C2α Knockdown Results in Rerouting of Insulin Signaling and Pancreatic Beta Cell Proliferation. Leibiger B et al. Cell Rep. 2015 Oct 6;13(1):15-22.
- Apolipoprotein CIII links islet insulin resistance to β-cell failure in diabetes. Åvall K et al. Proc Natl Acad Sci U S A. 2015 May 19;112(20):E2611-9.
- The paired basic amino acid-cleaving enzyme 4 (PACE4) is involved in the maturation of insulin receptor isoform B: an opportunity to reduce the specific insulin receptor-dependent effects of insulin-like growth factor 2 (IGF2). Kara I et al. J Biol Chem. 2015 Jan 30;290(5):2812-21.
- Ciliary dysfunction impairs beta-cell insulin secretion and promotes development of type 2 diabetes in rodents. Gerdes JM et al. Nat Commun. 2014 Nov 6;5:5308.
- Proinsulin C-peptide and insulin: Limited pattern similarities of interest in inter-peptide interactions but no C-peptide effect on insulin and IGF-1 receptor signaling. Henriksson M et al. Cell Mol Life Sci. 2006 Dec;63(24):3055-60.
- Short-term regulation of insulin gene transcription. Leibiger B et al. Biochem Soc Trans. 2002 Apr;30(2):312-7.
- Online monitoring of stimulus-induced gene expression in pancreatic beta-cells. Moede T et al. Diabetes. 2001 Feb;50 Suppl 1:S15-9.