Insulin Binding: Receptor Interactions, Dimerization, Hexamerization, and Other Molecules

Insulin primarily binds to the insulin receptor (INSR), but it can also interact with other receptors such as the insulin-like growth factor 1 receptor (IGF1R) and the insulin-like growth factor 2 receptor (IGF2R).

Insulin can bind to IGF1R, although with lower affinity compared to its binding to INSR. This interaction can activate downstream signaling pathways associated with IGF1R.

References:

1. Belfiore A. et al. Insulin receptor isoforms in physiology and disease: An updated view. Endocr Rev. 2017;38(5):379-431. doi: 10.1210/er.2017-00073.
2. Mosthaf L. et al. Functionally distinct insulin receptors generated by tissue-specific alternative splicing. EMBO J. 1990;9(9):2409-2413. PMID: 2196172.

On the other hand, insulin does not bind to IGF2R. IGF2R primarily interacts with insulin-like growth factor 2 (IGF2) and acts as a clearance receptor for this ligand.

References:

1. Liu B. et al. Insulin-like growth factor II (IGF-II) inhibits the expression and enzymatic activity of insulin degrading enzyme (IDE) in neuronal cells. PLoS One. 2011;6(10):e25016. doi: 10.1371/journal.pone.0025016.
2. Rechler MM. Insulin-like growth factor binding proteins. Vitam Horm. 1993;47:1-114. doi: 10.1016/s0083-6729(08)61039-0.

Insulin exists as a monomer under physiological conditions, but it can form dimers in certain circumstances. Dimerization of insulin occurs when two insulin molecules associate with each other through disulfide bonds.

References:

1. Ward CW. et al. Insulin and its receptor: Structure, function and evolution. Bioessays. 1988;9(3):77-82. doi: 10.1002/bies.950090302.
2. De Meyts P. The insulin receptor and its signal transduction network. Endocr Rev. 1994;15(2):135-170. doi: 10.1210/edrv-15-2-135.

Insulin can also form hexamers under certain conditions, such as when it is stored in the pancreatic beta cells or when it is formulated as a pharmaceutical preparation. Hexameric insulin is less active compared to monomeric or dimeric forms.

References:

1. Dodson GG. et al. The role of insulin in the structure and function of fibroblast growth factor 1. FEBS J. 2006;273(5):849-861. doi: 10.1111/j.1742-4658.2006.05117.x.
2. Smith GD. et al. The structure of hexameric insulins and the mechanism of hexamer dissociation. Acta Crystallogr D Biol Crystallogr. 2013;69(Pt 5):791-799. doi: 10.1107/S0907444913001538.

Insulin can also bind to other molecules, such as insulin-like growth factors (IGFs) and insulin-like growth factor binding proteins (IGFBPs), which regulate its bioavailability and activity.

References:

1. Frasca F. et al. Insulin receptor isoforms and insulin receptor/insulin-like growth factor receptor hybrids in physiology and disease. Endocr Rev. 2017;38(5):379-431. doi: 10.1210/er.2017-00073.
2. Baxter RC. Insulin-like growth factor (IGF)-binding proteins: Interactions with IGFs and intrinsic bioactivities. Am J Physiol Endocrinol Metab. 2000;278(6):E967-E976. doi: 10.1152/ajpendo.2000.278.6.E967.