Glucose binds to the insulin receptor affecting the mutual affinity of insulin and its receptor

Abstract

Insulin activity is sensitive to glucose concentration but the mechanisms are still unclear. An unexamined possibility is that the insulin receptor (IR) is sensitive to glucose concentration. We demonstrate here that insulin-like peptides derived from the IR bind glucose at low millimolar, and cytochalasin B at low micromolar, concentrations; several insulin-like IR peptides bind insulin at nanomolar Kd; and this binding is antagonized by increasing glucose concentrations. In addition, glucose and cytochalasin B bind to IR isolated from rat liver and increasing glucose decreases insulin binding to this IR preparation. The presence of GLUT 1 in our IR preparation suggests the possibility of additional glucose-mediated allosteric control. We propose a model in which glucose binds to insulin, the IR, and GLUT; insulin binds to the IR; and the IR binds to GLUT. This set of interactions produces an integrated system of insulin-dependent interactions that is highly sensitive to glucose concentration.

Experimental Test of L- and D-Amino Acid Binding to L- and D-Codons Suggests that Homochirality and Codon Directionality Emerged with the Genetic Code

“…The differences between the values of the expected and observed spectra at selected wavelengths (see below) were then determined and these differences were plotted against the concentration of the amino acid added to the oligonucleotide to provide a binding curve. Results are highly accurate and reproducible [19,23].…”

“…We adapted a method previously described for determining binding constants between biomolecules [19,23]. In essence, spectra of each oligonucleotide at a constant concentration and each amino acid at a series of increasingly dilute concentrations were obtained.…”

Estradiol Binds to Insulin and Insulin Receptor Decreasing Insulin Binding in vitro

“…This method has been used for decades by other investigators (62–65) as well as by the authors of this paper (55, 56, 66–69). …”

T Cell Receptor Variable Regions in Diabetes Bind to Each Other, to Insulin, Glucagon or Insulin Receptor, and to Their Antibodies

“…Significance of homologies was determined by two criteria: at least 5 identities in a stretch of 10 amino acids and/or an E value greater than 35 (a measure of the probability of p < 0.01 that equivalent homologies would be found in a random search of 10,000 protein sequences of equivalent length). The comparison of the insulin receptor with PTP-IA-2 was carried out in two ways: 1) using the entire insulin receptor sequence and 2) using two specific sequences from the insulin receptor that have been identified as insulin-binding regions [28] (see Table 1 for sequences). These two insulin receptor peptides ), IR 105-118 and IR 897-915 (SwissProt numbering from P06213), were synthesized and purified to at least 98% purity by the Mass Spectroscopy, Synthesis and Sequencing Facility of the Department of Biochemistry of Michigan State University and used as part of the studies described below to determine TCR affinity.…”

“…Other complementarities have also been reported. The insulin receptor has multiple regions that mimic insulin and glucagon, and the glucagon receptor has multiple regions that mimic glucagon and insulin [26][27][28], so that these receptors might also be targets of diabetic TCR. In addition, insulin and glucagon are complementary to each other and produce primary antibodies that are complementary, and so act like idiotype-antiidiotype pairs [29].…”