Journal ArticleDOI
Discovery of a small molecule insulin mimetic with antidiabetic activity in mice.
Bei Zhang,Gino Salituro,Deborah Szalkowski,Zhihua Li,Yan Zhang,Inmaculada Royo,Dolores Vilella,Maria Teresa Diez,Fernando Pelaez,Caroline Ruby,Richard L. Kendall,Xianzhi Mao,Patrick R. Griffin,Jimmy R. Calaycay,Juleen R. Zierath,James V. Heck,Roy G. Smith,David E. Moller +17 more
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TLDR
The discovery of a nonpeptidyl fungal metabolite (L-783,281) that acted as an insulin mimetic in several biochemical and cellular assays demonstrates the feasibility of discovering novel insulin receptor activators that may lead to new therapies for diabetes.Abstract:
Insulin elicits a spectrum of biological responses by binding to its cell surface receptor. In a screen for small molecules that activate the human insulin receptor tyrosine kinase, a nonpeptidyl fungal metabolite (L-783,281) was identified that acted as an insulin mimetic in several biochemical and cellular assays. The compound was selective for insulin receptor versus insulin-like growth factor I (IGFI) receptor and other receptor tyrosine kinases. Oral administration of L-783,281 to two mouse models of diabetes resulted in significant lowering in blood glucose levels. These results demonstrate the feasibility of discovering novel insulin receptor activators that may lead to new therapies for diabetes.read more
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Signaling--2000 and beyond.
TL;DR: The important findings in the history of signal transduction are adequately covered in many reviews, and I have therefore cited reviews that discuss the seminal papers.
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Bioprospecting for Microbial Endophytes and Their Natural Products
Gary A. Strobel,Bryn Daisy +1 more
TL;DR: Endophytic microorganisms reside in the living tissues of the host plant and do so in a variety of relationships, ranging from symbiotic to slightly pathogenic, which may produce a plethora of substances of potential use to modern medicine, agriculture, and industry.
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Sources of Mathematical Thinking: Behavioral and Brain-Imaging Evidence
TL;DR: A series of behavioral and brain-imaging experiments provides evidence for both sources of linguistic competence and mathematical intuition, and suggests that mathematical intuition may emerge from the interplay of these brain systems.
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New drug targets for type 2 diabetes and the metabolic syndrome
TL;DR: Emerging knowledge of key pathogenic mechanisms, such as the impairment of glucose-stimulated insulin secretion and the role of 'lipotoxicity' as a probable cause of hepatic and muscle resistance to insulin's effects on glucose metabolism, has led to a host of new molecular drug targets.
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Hypothalamic insulin signaling is required for inhibition of glucose production.
TL;DR: The results reveal a new site of action of insulin on glucose production and suggest that hypothalamic insulin resistance can contribute to hyperglycemia in type 2 diabetes mellitus.
References
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Journal ArticleDOI
Human insulin receptor and its relationship to the tyrosine kinase family of oncogenes
Axel Ullrich,John Richard Bell,Ellson Y. Chen,R. Herrera,L. M. Petruzzelli,Thomas J. Dull,Alane M. Gray,Lisa M. Coussens,Yu Cheng Liao,M. Tsubokawa,Anthony J. Mason,Peter H. Seeburg,C. Grunfeld,Ora M. Rosen,J. Ramachandran,J. Ramachandran +15 more
TL;DR: The entire 1,370-amino-acid sequence of the human insulin receptor precursor is deduced from a single complementary DNA clone, finding sequence homologies to human epidermal growth factor receptor and the members of the src family of oncogene products.
Journal ArticleDOI
The protein kinase encoded by the Akt proto-oncogene is a target of the PDGF-activated phosphatidylinositol 3-kinase
Thomas F. Franke,Sung-Il Yang,Tung O. Chan,Ketaki Datta,Andrius Kazlauskas,Deborah K. Morrison,David R. Kaplan,Philip N. Tsichlis +7 more
TL;DR: It is shown that Akt and the Akt-related kinase AKT2 are activated by PDGF, and it is suggested that the AkT PH domain may be a mediator of PI 3-kinase signaling.
Journal ArticleDOI
Inhibition of vascular endothelial cell growth factor activity by an endogenously encoded soluble receptor
TL;DR: The recombinant soluble human receptor binds vascular endothelial cell growth factor with high affinity and inhibits its mitogenic activity forascular endothelial cells; thus this soluble receptor could act as an efficient specific antagonist of vascular endothelium cell growthFactor in vivo.
Journal ArticleDOI
The human insulin receptor cDNA: The structural basis for hormone-activated transmembrane signalling
Yousuke Ebina,Leland Ellis,Kurt Jarnagin,Marc Edery,László Gráf,Eric Clauser,Jing-Hsiung Ou,Frank Masiarz,Yuet Wai Kan,Ira D. Goldfine,Richard A. Roth,William J. Rutter +11 more
TL;DR: A cloned approximately 5 kb cDNA (human placenta) contains the coding sequences for the insulin receptor; the nucleotide sequence predicts a 1382 amino acid precursor and the overall structure is reminiscent of the EGF receptor.
Journal ArticleDOI
Crystal structure of the activated insulin receptor tyrosine kinase in complex with peptide substrate and ATP analog.
TL;DR: The crystal structure of the phosphorylated, activated form of the insulin receptor tyrosine kinase in complex with a peptide substrate and an ATP analog has been determined and provides insights into tyrosin kinase substrate specificity and the mechanism of phosphotransfer.
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