scholarly journals Potentiation of Insulin-Mediated Glucose Lowering without Elevated Hypoglycemia Risk by a Small Molecule Insulin Receptor Modulator

PLoS ONE ◽  
2015 ◽  
Vol 10 (3) ◽  
pp. e0122012 ◽  
Author(s):  
Margaret Wu ◽  
Ge Dai ◽  
Jun Yao ◽  
Scott Hoyt ◽  
Liangsu Wang ◽  
...  
Keyword(s):  
Insulin Receptor ◽  
Small Molecule ◽  
Glucose Lowering ◽  
Receptor Modulator

Signaling Effects of Demethylasterriquinone B1, a Selective Insulin Receptor Modulator

ChemBioChem ◽  
2003 ◽  
Vol 4 (5) ◽  
pp. 379-385 ◽  
Author(s):  
Nicholas J. G. Webster ◽  
Kaapjoo Park ◽  
Michael C. Pirrung
Keyword(s):  
Insulin Receptor ◽  
Receptor Modulator ◽  
Demethylasterriquinone B1

scholarly journals Spectroscopic characterization of insulin and small molecule ligand binding to the insulin receptor

2002 ◽  
Vol 16 (3-4) ◽  
pp. 147-159 ◽  
Author(s):  
Morten Schlein ◽  
Svend Ludvigsen ◽  
Helle B. Olsen ◽  
Michael F. Dunn ◽  
Niels C. Kaarsholm
Keyword(s):  
Ligand Binding ◽  
Insulin Receptor ◽  
Small Molecule ◽  
Receptor Binding ◽  
Conformational Changes ◽  
Insulin Analogue ◽  
Three Dimensional ◽  
Insulin Binding ◽  
Spectroscopic Characterization ◽  
Spectroscopic Techniques

We have applied spectroscopic techniques to study two kinds of ligand binding to the insulin receptor. First, a fluorescently labelled insulin analogue is used to characterize the mechanism of reversible 1 :1 complex formation with a fragment of the insulin receptor ectodomain. The receptor induced fluorescence enhancement of the labelled insulin analogue provides the basis for stopped flow kinetic experiments. The kinetic data are consistent with a bimolecular binding event followed by a conformational change. This emphasizes the importance of insulin induced conformational changes in the activation of the insulin receptor. Second, the binding of fluorescein derivatives to the insulin receptor is studied. These small molecule ligands displace insulin from its receptor with micromolar affinity. The binding is verified by transferred NOESY NMR experiments. Their chromophoric properties are used to measure the affinity by UV-vis and fluorescence difference spectroscopies and the resulting Kdvalues are similar to those observed in the displacement receptor binding assay. However, these experiments and a stoichiometry determination indicate multiple binding sites, of which one overlaps with the insulin binding site. These two examples illustrate how spectroscopy complements biochemical receptor binding assays and provides information on ligand–insulin receptor interactions in the absence of three dimensional structures.

scholarly journals Small Molecule Insulin Receptor Activators Potentiate Insulin Action in Insulin-Resistant Cells

Diabetes ◽  
2001 ◽  
Vol 50 (10) ◽  
pp. 2323-2328 ◽  
Author(s):  
M. Li ◽  
J. F. Youngren ◽  
V. P. Manchem ◽  
M. Kozlowski ◽  
B. B. Zhang ◽  
...  
Keyword(s):  
Insulin Receptor ◽  
Small Molecule ◽  
Insulin Action ◽  
Insulin Resistant ◽  
Resistant Cells

scholarly journals Chemical induction of gut β-like-cells by combined FoxO1/Notch inhibition as a glucose-lowering treatment for diabetes

2021 ◽  
Author(s):  
Takumi Kitamoto ◽  
Yun-Kyoung Lee ◽  
Wendy M. McKimpson ◽  
Hitoshi Watanabe ◽  
Nishat Sultana ◽  
...  
Keyword(s):  
Small Molecule ◽  
Genetic Effect ◽  
Intestinal Epithelial ◽  
Diabetes Treatment ◽  
Chemical Induction ◽  
Enteroendocrine Cell ◽  
Glucose Lowering ◽  
Cell Conversion ◽  
Plasma Insulin Levels

Lifelong insulin replacement remains the mainstay of type 1 diabetes treatment. Genetic FoxO1 ablation promotes enteroendocrine cell (EECs) conversion into glucose-responsive β-like cells. Here, we tested whether chemical FoxO1 inhibitors can generate β-like gut cells. Pan-intestinal epithelial FoxO1 ablation expanded the EEC pool, induced β-like cells, and improved glucose tolerance in Ins2Akita/+ mice. This genetic effect was phenocopied by small molecule FoxO1 inhibitor, Cpd10. Cpd10 induced β-like cells that released insulin in response to glucose in mouse gut organoids, and this effect was strengthened by the Notch inhibitor, DBZ. In Ins2Akita/+ mice, a five-day course of either Cpd10 or DBZ induced insulin-immunoreactive β-like cells in the gut, lowered glycemia, and increased plasma insulin levels without apparent adverse effects. These results provide proof of principle of gut cell conversion into β-like cells by a small molecule FoxO1 inhibitor, paving the way for clinical applications.

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